1 s2.0 S0014299924005089 Main

European Journal of Pharmacology 980 (2024) 176819
Contents lists available at ScienceDirect
European Journal of Pharmacology

journal homepage: www.elsevier.com/locate/ejphar
Experimental models of Parkinson’s disease: Challenges and Opportunities

Roshan Lal a , Aditi singh b , Shivam watts a , Kanwaljit Chopra a, *
a
Pharmacology Division, University Institute of Pharmaceutical Sciences (UIPS), Panjab University, Chandigarh, 160014, India
b
TR(i)P for Health Laboratory, Centre for Excellence in Functional Foods, Department of Food and Nutritional Biotechnology, National Agri-Food Biotechnology Institute
(NABI), Knowledge City, Sector 81, SAS Nagar, Punjab, 140306, India
A R T I C L E I N F O A B S T R A C T
Keywords: Parkinson’s disease (PD) is a widespread neurodegenerative disorder occurs due to the degradation of dopa-
Animal models minergic neurons present in the substantia nigra pars compacta (SNpc). Millions of people are affected by this
Genetic models devastating disorder globally, and the frequency of the condition increases with the increase in the elderly
Lewy bodies
population. A significant amount of progress has been made in acquiring more knowledge about the etiology and
Neurotoxins
Neurodegeneration
the pathogenesis of PD over the past decades. Animal models have been regarded to be a vital tool for the
Nigrostriatal pathway exploration of complex molecular mechanisms involved in PD. Various animals used as models for disease
Parkinson’s disease monitoring include vertebrates (zebrafish, rats, mice, guinea pigs, rabbits and monkeys) and invertebrate models
(Drosophila, Caenorhabditis elegans). The animal models most relevant for study of PD are neurotoxin induction-
based models (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 6-Hydroxydopamine (6-OHDA) and agri-
cultural pesticides (rotenone, paraquat), pharmacological models (reserpine or haloperidol treated rats), genetic
models (α-synuclein, Leucine-rich repeat kinase 2 (LRRK2), DJ-1, PINK-1 and Parkin). Several non-mammalian
genetic models such as zebrafish, Drosophila and Caenorhabditis elegance have also gained popularity in recent
years due to easy genetic manipulation, presence of genes homologous to human PD, and rapid screening of
novel therapeutic molecules. In addition, in vitro models (SH-SY5Y, PC12, Lund human mesencephalic (LUHMES)
cells, Human induced pluripotent stem cell (iPSC), Neural organoids, organ-on-chip) are also currently in trend
providing edge in investigating molecular mechanisms involved in PD as they are derived from PD patients. In
this review, we explain the current situation and merits and demerits of the various animal models.
1. Introduction coming years (Dorsey et al., 2018). PD onset can be categorized as ju-
venile (age <21 yr), early-onset (21–50 yr), and late-onset (generally
Parkinson’s disease (PD) is a chronic neurodegenerative disorder <60 yr) (Rizek et al., 2016). The etiology of PD is obscure, but the
that affects movement and cognition. The hallmark pathological fea- complex interaction of genetic and environmental factors is considered
tures of PD are the loss of dopaminergic neurons in the SNpc and the as the cause of the disease (Chai and Lim, 2013). PD begins with the
accumulation of α-synuclein-positive Lewy bodies (LBs) in various brain degeneration of dopaminergic neurons in SNpc involving complex
regions, including the cerebral cortex, locus coeruleus, hypothalamus pathological mechanisms such as oxidative stress, neuroinflammation,
and nucleus basalis (Dawson, 2000; Hammond et al., 2007; Rai and mitochondrial impairment, misfolded protein accumulation, and neural
Singh, 2020). According to Global Burden of Disease study (2016) PD is apoptosis (Fig. 1) (Fujimaki et al., 2014). PD patients develop diverse
the second most prevalent neurodegenerative disorder after Alzheimer’s motor and sensory symptoms. Motor symptoms include bradykinesia,
disease, and affected more than 6 million individuals from 1990 to 2016 hyperkinesia, and akinesia. Sensory symptoms such as internal tremors,
(Dorsey et al., 2018). Some studies projected the number to double to restless leg syndrome, numbness, pain paresthesia, and visual distur-
>12 million as PD is currently the fastest-growing neurodegenerative bances. Other symptoms, include paucity of normal facial expression
disorder (Rossi et al., 2018). In India, nearly 0.58 million people are (hypomania), decreased voice volume (hypophonia), drooling,
affected by this devastating disorder and numbers will increase in the decreased size (micrographia) and speed of handwriting, decreased
* Corresponding author. Professor of Pharmacology Pharmacology Research Laboratory University Institute of Pharmaceutical Sciences (UIPS) UGC Centre of
Advanced Studies, Panjab University, Chandigarh, 160 014, India.
E-mail addresses: [email protected] (R. Lal), [email protected] (A. singh), [email protected] (S. watts), [email protected], k.
[email protected] (K. Chopra).
https://doi.org/10.1016/j.ejphar.2024.176819
Received 7 September 2023; Received in revised form 29 May 2024; Accepted 17 July 2024
Available online 18 July 2024
0014-2999/© 2024 Published by Elsevier B.V.
R. Lal et al. European Journal of Pharmacology 980 (2024) 176819
stride length during walking etc. (Dauer and Przedborski, 2003). limitations of present therapies, there is a need to explore the molecular
The neuropathological progression of PD can be well understood by mechanisms with robust animal models for the development of novel
Braak’s hypothesis. According to this hypothesis, the sequence of the therapeutic options for PD. So far, an understanding of the initiation and
disease starts in the olfactory bulb and medulla, and symptoms such as progression of neurodegenerative processes in PD has not developed,
rapid eye movement (REM) sleep behavior disorder, and decreased but over the past two decades, extensive research has been conducted in
smell were observed in PD patients in the initial stage. Later on, as the various in vitro, in vivo experimental models. Moreover, brain autopsy
disease progresses to other midbrain and basal forebrain areas, investigations in PD patients resulted in a better understanding of the
including the SNpc, the characteristic PD motor symptoms appears. disease pathology (Cicchetti et al., 2005).
(Braak et al., 2003). PD can be further classified into three heteroge- Animal models are important experimental tools due to their ability
neous subgroups based on motor and non-motor characteristics. The to recapitulate the disease pathogenesis and screening of novel thera-
first can be defined as mild motor predominant which is early in onset, peutic strategies for the diagnosis and treatment of human disease (Bové
slow progressing, shows good response to treatment and includes motor et al., 2005). To investigate the pathogenesis of PD, three main cate-
and non-motor symptoms. The second is intermediate which onsets at gories of animal models are used: neurotoxic, pharmacological and ge-
middle age, and has a good to excellent response to treatment (Chaud- netic. However, no single model reproduces the complete pathogenesis
huri et al., 2010). The third is diffuse malignant which is indicated by of the disease. Neurotoxin models are the most common animal models
baseline motor symptoms of rapid eye movement sleep behavior helpful in screening and validation of novel therapies targeting motor
disturbance, mild cognitive dysfunction, orthostatic hypotension, symptoms of PD. Toxin-based models lack the ability to replicate the
poorer levodopa response, more prominent dopaminergic dysfunction pathology and cell death that are detected in other regions of the brain.
on dopamine transporter (DAT) single photon emission tomography Hence, other models of PD established on genetic deformations have
(DaT SPECT), and greater atrophy in specific magnetic resonance im- emerged on top in the past decade. The significant advantage of genetic
aging (MRI) voxels, low amyloid-β and amyloid-β/t-tau ratio in the ce- models is the evaluation of over-expression of α-synuclein, LRRK2,
rebrospinal fluid, and rapid progression (Berg et al., 2015; Hawke et al., Parkin, Pink1 and DJ-1 in rats and mice (Hammond et al., 2007). In
1991; Howell and Schenck, 2015; Suwijn et al., 2015). addition, other non-mammalian genetic models such as zebrafish,
Clinically, PD is diagnosed by monitoring some cardinal motor signs drosophila, and C. elegans have been developed recently because of easy
such as postural instability, bradykinesia, rigidity, and tremor. Today genetic amenability, genetic similarities with human genome, and rapid
75% of PD cases are confirmed by autopsy. Imaging techniques such as screening of therapeutic drugs.
MRI, SPECT, and positron emission tomography (PET) can be utilized to An ideal experimental model should preferably meet these three
monitor brain imaging of structural and functional changes. Secondary conditions. it, firstly, should summarize maximum sporadic PD,
and atypical forms of parkinsonism can be differentiated from PD using including its progressiveness and pathological marker (replication of
structural MRI. However, no neuroimaging technique is particularly cytoplasmic LB-like inclusions). Secondly, the drug regimen should be
advised for daily use in clinical practice for PD (Gelb et al., 1999; Pagano administered as soon as the DA neurons’ neurodegeneration has begun
et al., 2016). Levodopa remains the most effective treatment for PD, but to mimic the model clinically. Thirdly, the verification of the efficacy of
its long-term use is limited by motor complications, such as fluctuations model should be attained from non-human primate models (Meissner
between akinesia (rapid return of muscle rigidity) and dyskinesias et al., 2004). Consequently, animal models provide a clear picture of PD
(abnormal involuntary movements). Dopamine (DA) agonists, anticho- and predict potential successful treatment for the disease (Cannon and
linergics, amantadine, and monoamine oxidase (MAO) inhibitors are Greenamyre, 2010). Despite the advantages, animal models fail to
further therapy options (Deng et al., 2018; Rizek et al., 2016). Due to recapitulate the disease condition perfectly due to various limitations
Fig. 1. Schematic representation of the pathogenic mechanisms that trigger DA neuron death, and the action of different genes and compounds in PD. Top insets-
mitochondrial dysfunction and cell death influenced by various environmental, genetic, and biological factors in PD. Bottom insets-evolutionary hierarchy of animal
models for development of disease-modifying therapies in PD.
2
like the disease state being inappropriately modeled, unclear effect of administered systemically, 6-OHDA shows high affinity for DAT and
route of exposure on pathogenesis, and due to variation in biochemistry leads to destruction of sympathetic neuronal nerve terminals present in
and anatomy between animals and humans (Cicchetti et al., 2009). the peripheral nervous system (Bové and Perier, 2012). Furthermore,
the systemic administration of 6-OHDA fails to induce parkinsonism-like
2. Toxin models symptoms as it is unable to cross the BBB. Therefore, it is injected
unilaterally into the SNpc, medial forebrain bundle, or striatum (Blesa
2.1. 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine and Przedborski, 2014). Within the first 12 h of injection, dopaminergic
neurons begin to die and the depletion of dopaminergic nerve terminals
The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was first is established within 2–3 days (Blandini and Armentero, 2012).
found to be an effective DA neurotoxin in 1982, when some young drug Neurotoxicity in the 6-OHDA model is based on a robust inhibitory effect
addicts self-administered it thinking it to be synthetic heroin, and of toxicant on mitochondrial complexes I and IV causing the metabolic
developed irreversible and severe parkinsonian symptoms (Terzioglu deficiency (Table 1). Hence, neurons are unable to exert their normal
and Galter, 2008). As a lipophilic molecule, the narcotic drug analog physiological functions, and neuronal degeneration begins (Deumens
MPTP can easily cross the blood-brain barrier (BBB). In the brain, et al., 2002). 6-OHDA is the prototypical model, and the lesions are
monoamine oxidase type B (MAO-B) enzyme first converts MPTP to highly reproducible. It adds extra value in the evaluation of neuro-
1-methyl-4-phenyl-2, 3-dihydropyridium (MPDP+), which is then protective efficacy of novel PD pharmacotherapies as it induces unilat-
further deprotonated to produce the pyridium species, 1-methyl-4-phe- eral lesions and prompts turning behavior in response to direct or
nyl-pyridinium (MPP+) (Dawson and Dawson, 2010; Smeyne and indirect activators of DA receptors (Blandini and Armentero, 2012). This
Jackson-Lewis, 2005). DAT and norepinephrine (NE) transporters model is of great importance in studying the motor aspects of PD.
rapidly uptake released MPP+ from extracellular space into the dopa- However, 6-OHDA is responsible for the rapid depletion of DA and fails
minergic and NE neurons resulting in the generation of reactive oxygen to mimic the progressive loss of dopaminergic neurons in PD. Moreover,
species (ROS), which finally contributes to auto toxicity in SNpc dopa- it disturbs other brain areas like locus coeruleus and fails to form the
minergic and NE neurons (Meredith and Rademacher, 2011). Studies major pathological hallmark of PD i.e. LBs, cytoplasmic inclusions seen
have shown that expression of DAT is critical in MPTP toxicity as in patients (Betarbet et al., 2002; Meredith and Kang, 2006; Schwarting
DAT-deficient mice show no toxicity symptoms when exposed to MPTP and Huston, 1996).
(Takahashi et al., 1997). In dopaminergic neurons MPP+ present in
axoplasm forms complex with neuromelanin and is transported by ve- 2.3. Paraquat
sicular monoamine transporter type 2 (VMAT-2) (Gainetdinov et al.,
1998). Furthermore, MPP+ causes mitochondrial complex-I inhibition Paraquat or N,N′-dimethyl-4,4′-bipyridinium dichloride (systematic
resulting in enormous ROS production and impaired mitochondrial name), also known as methyl viologen is a widely used herbicide that
respiration and ATP synthesis. ROS damaged mitochondria leads to was reported as a neurotoxicant based on reports of epidemiological
release of cytochrome C which forms a complex with pro-caspase-9 and studies and suggested to induce parkinsonism as it is structural analog of
apoptosis protease activating factor-1 which further leads to dopami- MPP+ (Di Monte et al., 1986; Uversky and research, 2004). It exerts
nergic neurodegeneration in SNpc and striatum (Basil et al., 2017; toxic effects by inducing cellular diaphorase (Nitric oxide
Javitch et al., 1985; Langston et al., 1983; Schmidt and Ferger, 2001). synthase)-mediated redox cycling (Bonneh-Barkay et al., 2005; Gubel-
MPTP is regarded as the gold standard model for understanding the lini and Kachidian, 2015). Paraquat penetrates the BBB despite its high
mechanisms involved in nigral neuronal apoptosis (Lin et al., 2020). polarity through neutral amino acid transporter and acts by inhibiting
Furthermore, MPTP model offers several advantages. Firstly, MPTP is mitochondrial complex-I. However, unlike MPP+, it acts by the gener-
the sole neurotoxin model that depicts the clinical picture of PD and its ation of ROS, increasing oxidative stress resulting in impaired redox
symptoms in humans, rodents and monkeys. Secondly, no special cycling of glutathione and thioredoxin (Fig. 1) (Niso-Santano et al.,
equipment is involved, such as stereotaxic frame, as in other neurotoxin 2010). Various ROS are produced like superoxide radical (O2‾), hy-
models like 6-OHDA, rotenone, etc. In addition, MPTP produces repro- droxyl radical (HO˙), and hydrogen peroxide (H2O2), which further
ducible and authentic lesions of the dopaminergic pathways produce deleterious effects on proteins, lipids, RNA, and DNA (Jack-
post-systemic administration (Jackson-Lewis et al., 2012; Jackson-Lewis son-Lewis et al., 2012). Manganese ethylene-bis-a-dithiocarbamate
and Przedborski, 2007). However, MPTP-induced mice models are (MANEB), a fungicide as well as an inhibitor of the reuptake mecha-
strain and age-dependent. It causes acute injury to mice due to mice’s nism of DA and glutamate transport, is co-administered with paraquat to
impulsive recovery, resulting in difficulty in evaluating the long-term enhance its toxic effects (Takahashi et al., 1989). Paraquat model is
efficiency of therapeutics (Le et al., 2014). MPTP lacks the authentic highly significant in exploring PD pathology due to its ability to develop
mark of PD, i.e., production of LBs, and this model is resistant to rats, LB-like structures in dopaminergic neurons, and the upregulation of
which produces no significant impairment in DA neurons (Blesa and α-synuclein in the SNpc (Inden et al., 2011; Kumar et al., 2016; See et al.,
Przedborski, 2014; Jackson-Lewis et al., 2012). Furthermore, MPTP fails 2022). However, this model does not define the molecular link between
to replicate the behavioral features of human PD (Lindholm et al., 2016). oxidative stress and neuronal death. Hence, the understanding of para-
The predominant use of male animals is also a disadvantage as previous quat in PD pathology is often limited to the study of the formation of LBs
research data shows that estrogen might be protective against MPTP in dopaminergic neurons along with the role of α-synuclein in PD (Blesa
causing sex-influenced variability in dopaminergic neuron loss (Dluzen et al., 2012; See et al., 2022).
et al., 1996). The current research studies suggest sex-specific differ-
ences in disease progression and medication response in PD (Cerri et al., 2.4. Rotenone
2019).
Rotenone is an insecticide and pesticide; a natural compound
2.2. 6-Hydroxydopamine extracted from the Lonchocarpus and Derris genera’s roots; having
cytotoxic properties and used as a fish and insect poison for years. In late
6-Hydroxydopamine (6-OHDA) is a hydroxylated analog of the DA 1990, it emerged as a possible environmental toxin for PD (Bezard and
originally isolated by Senoh and Witkop (1959) (Senoh et al., 1959). Przedborski, 2011). It is used as an insecticide in vegetable gardens and
Currently, it is one of the most vital in vivo and in vitro neurotoxin models it also controls nuisance fish populations. In humans, oral, dermal, and
used in central catecholaminergic neurotransmitters, including the inhalational exposure to rotenone can be dangerous. Recently, exposure
nigro-striatal system (Schober, 2004; Yuan et al., 2005). When to this insecticide has been associated with amplified risk of PD
3
Table 1
Neurotoxins and pharmacological models of PD.
MODEL Animals MECHENISM ADVANTAGES DISADVANTAGES REFRENCES
used
MPTP Monkey, Induces the production of ROS, Sole neurotoxin model that depicts It provides acute injury to mice (Lu et al., 2018; Schmidt
Rat, Mice, mitochondrial dysfunction, the clinical picture of PD and its due to mice’s impulsive recovery, and Ferger, 2001; Zheng
Zebrafish decreases ATP production, symptoms in both humans and resulting in difficulty in et al., 2018)
degeneration of TH monkeys. Does not require special evaluating long-term efficiency
immunoreactive dopaminergic equipment and technique is of therapeutics.
neurons in SNpc, α-synuclein involved.
aggregation Systemic administration of MPTP MPTP lacks the authentic mark of
produces reproducible and PD, i.e., production of LBs.
authentic lesions of the
dopaminergic pathways.
6-OHDA Rat, Mice, 6-OHDA-induced neurotoxicity 6-OHDA is the prototypical model, Special surgical instrument (Betarbet et al., 2002;
Zebrafish based on a robust inhibitory effect and the lesion obtained with this required, 6-OHDA induction Deumens et al., 2002;
on I and IV mitochondrial model is highly reproducible, useful results in rapid depletion of DA Meredith and Kang, 2006;
Complexes, degeneration of in neurobehavioral analysis and and so, it fails to mimic the Prajapati et al., 2017;
dopaminergic neurons, TH+ screening of therapies designed to progressive loss of dopaminergic Zheng et al., 2018)
neurons and decreased levels of protect dopaminergic neurons neurons in PD, disturbs other
DA in SNpc regions of the brain like locus
coeruleus and fails to lead the
formation of LBs.
Paraquat Mice, Rat Penetrates the BBB through Develop LBs like structures in Does not define the molecular (Blesa et al., 2012; Kumar
neutral amino acid transporter, dopaminergic neurons of the SNpc link between oxidative stress and et al., 2016;
affects pentose phosphate as well as to produce upregulation cell death, mortality rate is very Muthukumaran et al.,
pathway, inhibits mitochondrial of α-synuclein. high in experimental animals 2014; See et al., 2022)
complex I, increases oxidative
stress, damages nucleic acids and
proteins, LBs formation
Rotenone Selective degeneration of the Imitates all biochemical hallmarks Disparity regarding the (Bisbal and Sanchez,
nigrostriatal DA pathway, seen in PD patients. percentage of animals that 2019; Blesa et al., 2012;
α-synuclein aggregation, impaired develop dopaminergic Cannon et al., 2009;
ubiquitin-proteasome formation, nigrostriatal lesions and the Terron et al., 2018)
and intracellular LB-like severity of that lesion, difficult to
inclusions. replicate and reproduce in
experimental animals due to the
high morality of rotenone in rats,
laborious and intensive model.
Reserpine Rat, Inhibits VMAT2 in CNS, Depletion Cause 85% loss of DA CNS. No dopaminergic cell (Goldstein et al., 1975;
Zebrafish, of monoamines such as 5-HT, degeneration in SNpc allows Rijntjes and Meyer, 2019;
Drosophila noradrenaline and DA in CNS short-term drug testing and Santos et al., 2013;
results in a wide range of motor restricts the model to evaluate Sebastianutto and Cenci,
damage that resembles PD. novel therapeutic drugs that offer 2018)
symptomatic treatment,
Haloperidol Monkey, Antagonize postsynaptic DA D2 Preclinical evaluation of Failed to reproduce full spectrum (Atack et al., 2014; Luthra
Rat, Mice, receptor sand to a lesser extent D1 symptomatic efficacy of non- pathophysiology of PD. et al., 2009; Sebel et al.,
Zebrafish receptor which inhibits dopaminergic pharmacotherapies. 2017; Tarrants et al.,
nigrostriatal DA resulting in 2010)
abnormal firing in basal ganglia
neurons.
Manganese Mice, Morphological, neurochemical, Excess Mn in specific brain regions Mn shows other parallel side (Ordonez-Librado et al.,
Zebrafish and behavioral changes leads to the gradual degeneration of effects apart from neurotoxicity 2011; Nadig et al., 2022;
reminiscent of those observed in neurons. Kwakye et al., 2015)
PD, deficiency in motor function.
Trichloroehylene Mice, Rats Dopaminergic neurodegeneration TCE-induced activation of LRRK2 Route of administration in the (Dorsey et al., 2023; De
and mitochondrial complex I kinase contributed to the selective animal models does not reflect Miranda et al., 2020,
activity inhibition in substantia toxicity of dopaminergic neurons. inhalation route which is the 2021)
nigra, activation of wildtype major contributor of TCE toxicity
LRRK2 resulting in dopaminergic in humans.
dysfuntion, oxidative stress,
endolysosomal dysfunction,
α-synuclein accumulation.
Endosulfan Mice Exposure during gestation and During specific Additional evaluation procedures Wilson et al. (2014)
lactation led to diminished DAT neurodevelopmental phases, are required to validate this
and tryrosine hydroxylase levels in exposure causes increased model
the striatum. suseceptibility of DA neurons to
damage.
Copper sulfate Rodents Cellular internalization of Both in vitro and in vivo studies have Despite having the ability to (Li et al., 2023; Montes
α-synuclein fibrils, intracellular demonstrated the Parkinson’s- catalyze production of ROS, et al., 2014; Karpenko
aggregation of α-synuclein, and specific neurotoxicity arising from neither elevated concentrations et al., 2023)
the subsequent release of mature the accumulation of copper ions in in the environment nor high
fibrils into the extracellular space the central nervous system dietary levels are linked to an
increased risk of PD.
Diquat Cell Culture Causes free radical generation Causes acute intracerebral Even at high doses, it does not Nisar et al. (2015)
through mitochondrial inhibition hemorrhage in the white matter and induce significant changes in
brainstem α-synuclein or mitochondrial
(continued on next page)
4
Table 1 (continued )
MODEL Animals MECHENISM ADVANTAGES DISADVANTAGES REFRENCES
used
activity observed in typical

idiopathic LBs in PD cases.
Trifluralin Cell Culture Trifluralin induces α-synuclein Causes mitochondrial dysfunction It does not result in increased (Paul and Ritz, 2022)
fibril formation in a cell-free phosphorylated α-synuclein.
system
(Johnson and Bobrovskaya, 2015). Rotenone is lipophilic and crosses reserpine model reproduces major biochemistry of PD and induces
BBB leading to the formation of α-synuclein fibrils (Bisbal and Sanchez, clinical features such as akinesia and limb rigidity, no dopaminergic cell
2019; Inden et al., 2011). Rotenone specifically inhibits mitochondrial degeneration in SNpc was reported (McGregor and Nelson, 2019;
complex I in DA neurons and causes selective degeneration of nigros- Milosevic et al., 2019). In addition, striatal DA depletion and limb ri-
triatal DA pathway, ubiquitin formation, and intracellular LB-like in- gidity peak after 1–2 h and persist up to 24h reserpine post-induction
clusions. This model attains the clinical hallmark of PD by systemic allowing short-term drug testing and restricting the model to evaluate
inhibition of complex-I, indicating that the nigrostriatal DA pathway is novel therapeutic drugs that offer symptomatic treatment (Duty et al.,
selectively dependent on complex-I inhibition (Alam and Schmidt, 2002; 2011; Goldstein et al., 1975; Milosevic et al., 2019). However, this
Betarbet et al., 2000; Bisbal and Sanchez, 2019; Degli Esposti et al., model has been proven very beneficial in accessing the efficacy of both
1983). The rotenone model produces many PD-like characteristics, such dopaminergic and non-dopaminergic drugs in current clinical use for
as oxidative damage, activation of microglial cells, selective nigros- symptomatic treatment of PD (Kasabova-Angelova et al., 2020; Maj
triatal dopaminergic degeneration, α-synuclein accumulation, forma- et al., 1997; Miyagi et al., 1996).
tion of LB-like inclusions, impairment of mitochondrial and
ubiquitin-proteasome function (Betarbet et al., 2002; Bisbal and San-
2.6. Haloperidol
chez, 2019; Cannon et al., 2009). However, the use of the rotenone
model is limited by its disparity regarding the percentage of animals that
Haloperidol, a neuroleptic agent, functions by primarily antago-
developed dopaminergic nigrostriatal lesions as well as the severity of
nizing postsynaptic DA-D2 and D1 receptors to a lesser extent. It inhibits
the lesion. Furthermore, it is a laborious and intensive model and results
nigrostriatal DA resulting in abnormal firing in basal ganglia neurons
are difficult to replicate and reproduce in rats due to the high morality
(Luthra et al., 2009). Haloperidol (0.5–5 mg/kg, i.p.) produces symp-
on rotenone administration (Betarbet et al., 2002; Blesa et al., 2012;
toms such as muscle rigidity and catalepsy within 6h post-injection (Yael
Miyazaki et al., 2020).
et al., 2013). Recent studies demonstrate that haloperidol administra-
tion leads to a decrease in DA, 5-HT, and noradrenaline concentration in
striatum (Tarrants et al., 2010). However, elevated levels of extracel-
2.5. Reserpine
lular glutamate have been reported in entopeduncular nucleus after
haloperidol administration. These observations increase the validity of
Reserpine, a Rauwolfia serpentine alkaloid, blocks the VMAT2, im-
this model as a neurobiological mimic of PD (Kulkarni et al., 2009;
pairs the synaptic reuptake, and is involved in release of monoamine
Sanberg et al., 1988; Stayte and Vissel, 2014; Tarrants et al., 2010). The
neurotransmitters in the central nervous system (CNS) (Rijntjes and
novel therapeutic compounds with anti-parkinsonian potential are
Meyer, 2019). This was one of the first animal models to simulate the
evaluated in this model to determine the extent to which they reverse
neurochemical alterations of PD. In the late 1950s, Carlsson et al.
muscular rigidity and catalepsy in bar test (Sebel et al., 2017). Similar to
established a link between PD and reserpine by demonstrating that
reserpine model, haloperidol model also failed to reproduce the major
L-DOPA alleviates the akinetic state in reserpine-treated rats. This effect
pathophysiology of PD. This is the model of choice for assessing the
was later reproduced in humans which established reserpine-treated
effectiveness of emerging non-dopaminergic drugs such as
rodent model as a robust screening tool for analyzing efficacy of po-
mGlu4-positive allosteric modulators, adenosine A2A/A1 antagonists,
tential therapeutic drugs for PD (Carlsson et al., 1957, 1989; Leão et al.,
and mGlu7 agonists in PD (Neustadt et al., 2009; Niswender et al., 2008;
2015). Reserpine administered at the dose of 4–5 mg/kg i.p, inhibits the
Sanberg et al., 1988; Sebastianutto and Cenci, 2018; Shook et al., 2010;
VMAT2, leading to the depletion of monoamines such as 5-hydroxytryp-
Zheng et al., 2018).
tamine (5-HT), noradrenaline and DA in CNS, resulted in a wide range of
motor damage resembling PD, which includes hyperkinesia, rigidity of
limbs, akinesia and oral tremors (Dekundy et al., 2015; Leão et al., 2015; 2.7. Other neurotoxin-induced models
Rahman et al., 2020; Rijntjes and Meyer, 2019). In addition, reserpine
also produces other symptoms such as recognition memory impair- Neurotoxic pesticides such as organophosphates, carbamates, or-
ments, anxiety-like behavior, depressive and anhedonia-like behaviors, ganochlorines, and insecticides tend to interfere with the ion channels
and nociceptive sensitization observed in the open field, catalepsy bar, and neuronal transmission in the nervous system. Exploration of PD and
and oral movement tests. Motor impairments precede cognitive im- other neurodegenerative disorders associated with occupational expo-
pairments accessed in novel object recognition test attributed to sure to these chemicals has been widely done. The study of pesticide
neuronal alteration leading to increased lipid peroxidation and reduc- exposure became prominent when MPTP was implicated in the induc-
tion in TH immuno-staining in the striatum; this resembles the patho- tion of PD in humans. The primary mechanism triggered upon their
physiology of PD (Bisong et al., 2010; Bispo et al., 2022; Fernandes et al., induction is the faulty functioning of mitochondria and conformational
2008; Li et al., 2022; Santos et al., 2013). In addition, studies have changes in α-synuclein, precipitating Parkinsonian symptoms (Islam
shown 85% DA loss in the SNpc and >95% DA decline in the striatum 2h et al., 2021). In a study conducted to assess the in vitro toxicity profile of
post-induction. However, DA levels returned to ~30% within 24 h of the chemicals via Tox21 assay, naled, endosulfan, folpet, and propargite
induction, whereas declined striatal levels remained at >95% up to 24h showed increased activity. These along with dicofol and trifluralin,
(Heeringa and Abercrombie, 1995; Robledo and Feger, 1991). Reserpine showed mitochondrial membrane permeability, leading to mitochon-
induction also increases subthalamic nucleus (STN) firing and extra- drial dysfunction (Narayan et al., 2017; Paul and Ritz, 2022). In another
cellular glutamate levels in basal ganglia regions that mimic the pa- study conducted to investigate pesticides as a risk factor for the devel-
thology of PD (Benazzouz et al., 2002; Hutchison et al., 1998). Although opment of PD, the above-mentioned pesticides caused cell death more
5
than three standard deviations above the control. Some of them led to and cotton, contains two stereoisomers, α and β endosulfan, in a ratio of
neurite degeneration, besides neuronal cell death. These pesticides do 70:30 in its commercial form. This chemical poses risks to mammals,
not belong to any common toxicity category and have a different exhibiting reproductive and neurotoxic effects (Camacho-Morales and
structure, spanning over the classes of insecticides, herbicides, and Sánchez, 2015). The impact of endosulfan exposure on the nigrostriatal
fungicides (Paul and Ritz, 2022). A recent study also found trifluralin to DA system, crucial for neurological function, is significant. During spe-
have an increased risk of being a causative agent for PD in people not cific phases of neurodevelopment, exposure to endosulfan leads to
using chemical-resistant gloves as a preventive measure in comparison changes in dopaminergic neurons, rendering them more susceptible to
to glove wearers (Shrestha et al., 2020). These studies on cell lines, subsequent damage. Utilizing an in vivo developmental model, it was
animal models, and human subjects display the risk associated with the observed that exposure to endosulfan during gestation and lactation
exposure of these chemicals to the body during occupational activities. resulted in diminished levels of DAT in the striatum of male mice
offspring (Wilson et al., 2014). These indicators are also observed in PD,
2.7.1. Manganese (Gopinath et al., 2022), implicating endosulfan in producing PD-like
Manganese (Mn) toxicity presents as a combination of motor and symptoms.
sensory disruptions alongside neuropsychiatric and cognitive impair-
ments. An excess of Mn in specific brain regions, such as the globus 2.7.4. Copper sulfate
pallidus, subthalamic nucleus, substantia nigra, and striatum, critical in Copper sulfate pentahydrate is primarily used in agriculture as a
controlling various functions, leads to a gradual degeneration of neu- fungicide, while outside the realm of agriculture, it serves as an algae-
rons. Prolonged exposure to Mn concentrations exceeding 1 mg/m3, cide and herbicide to manage invasive aquatic plants. The copper (Cu+2)
particularly in occupational settings, becomes a potential contributor to ions released from copper sulfate, bind to specific proteins, resulting in
PD. The onset of occupational Mn-induced Parkinsonism is linked to the denaturation and subsequent cell damage. The Cu+2 ions, aside from
prolonged inhalation of Mn fumes and dust (Kwakye et al., 2015). their intended effects, have the potential to generate free radicals,
Research studies aimed to assess the effects of inhaling a combination of causing oxidative and inflammatory stress and disrupting mitochondrial
Mn2+ and Mn3+ on mice, intending to establish a distinctive animal function. Additionally, α-synuclein exhibits a pronounced affinity for
model for PD. The objective was to induce bilateral and progressive copper binding. This interaction has been observed to induce the olig-
dopaminergic cell death, correlate these alterations with motor distur- omerization of α-synuclein and expedite the prion-like propagation of
bances, and evaluate the impact of L-DOPA treatment on behavior. The α-synuclein fibrils. This process is facilitated by promoting the cellular
findings convincingly demonstrated that the inhalation of the internalization of α-synuclein fibrils, intracellular aggregation of
Mn2+/Mn3+ mixture resulted in morphological, neurochemical, and α-synuclein, and the subsequent release of mature fibrils into the
behavioral changes reminiscent of those observed in PD, providing a extracellular space, thereby initiating further propagation. Conse-
valuable experimental model for studying this neurodegenerative dis- quently, both in vitro and in vivo studies have demonstrated the PD-
ease (Ordonez-Librado et al., 2011). In a separate study, researchers specific neurotoxicity arising from the accumulation of Cu+2 ions in
developed a dependable PD model in zebrafish using manganese chlo- the CNS (Li et al., 2023).
ride (MnCl2). Through prolonged exposure to MnCl2 over 21 days, adult
zebrafish displayed symptoms resembling both non-motor and motor 2.7.5. Diquat
aspects of PD. MnCl2-treated fish exhibited a reduction in locomotor Diquat [6,7-dihydrodipyrido[1,2-a:2′,1′-c]pyrazine-5,8-diium dibro-
activity compared to the control group, indicating a deficiency in motor mide], serves as a non-selective contact herbicide renowned for its high
function (Nadig et al., 2022). However, studies have displayed con- toxic capability (Basilicata et al., 2022). It is a potent non-selective
flicting findings regarding the mixed effects of Mn on nigral and striatal herbicide marketed as a paraquat alternative exhibiting high toxicity
DA levels in Mn-treated animals. These variations may link to differ- and is widely used in agriculture and homes. Structurally similar to
ences in exposure methods, doses, duration, Mn concentration, animal paraquat, diquat is implicated in PD and causes acute intracerebral
age, and other factors, highlighting the complexity of Mn toxicity and hemorrhage, particularly in the white matter and brainstem. Its toxic
suggesting gaps in our understanding of its mechanisms (Ordonez-Li- mechanism involves free radical generation through mitochondrial in-
brado et al., 2011). hibition, leading to caspase-independent cell death resembling pro-
grammed necrosis. Despite its in vitro toxicity, even at high doses diquat
2.7.2. Trichloroethylene does not induce significant changes in α-synuclein or mitochondrial
Trichloroethylene (TCE), a simple six atoms colorless molecule, has activity observed in typical idiopathic LBs in PD cases. If diquat con-
countless applications, from decaffeinating coffee and degreasing metal tributes to PD, it might be associated with rarer forms of PD lacking
parts to serving as a solvent in dry cleaning. It was considered a potential prominent LBs (Nisar et al., 2015).
hazardous neurotoxin when a study linked TCE exposure to PD and
Parkinsonism in 1969. Subsequent investigations involving four case 2.7.6. Trifluralin
studies and a total of eight individuals established a connection between Trifluralin, a member of the dinitroaniline herbicide family, has been
occupational exposure to TCE and PD. TCE poses environmental risks by identified as a catalyst for dopaminergic neuron toxicity, leading to
contaminating outdoor air, seeping into groundwater, and infiltrating disruptions in mitochondrial function. Unlike its impact on plant cells
indoor spaces. Animal models such as OF1 mice and Fisher 344 rats have and protozoa, where it hinders cell division through microtubule de-
been instrumental in illustrating the impact of TCE, revealing mito- polymerization, trifluralin does not bind to mammalian or human
chondrial complex I activity inhibition and dopaminergic neuro- tubulin. The observed effects on neuronal respiration align with a well-
degeneration in the SNpc (Dorsey et al., 2023). Additionally, chronic established body of literature linking mitochondrial dysfunction to PD.
systemic exposure to TCE in aged rats activated wildtype LRRK2, Further investigation is needed to determine if trifluralin’s impact on
resulting in nigrostriatal dopaminergic dysfunction. This exposure neurons is α-synuclein-dependent. Interestingly, trifluralin induces
induced increased oxidative stress, endolysosomal dysfunction, and α-synuclein fibril formation in a cell-free system yet does not result in
α-synuclein accumulation, implying that the TCE-induced activation of increased phosphorylated α-synuclein. This discrepancy could be
LRRK2 kinase contributed to the selective toxicity of dopaminergic explored further using more manageable cell lines, including isogenic
neurons (De Miranda et al., 2021). mutation-corrected and α-synuclein knockout lines (Paul and Ritz,
2022).
2.7.3. Endosulfan
Endosulfan, an insecticide widely used on crops such as coffee, tea,
6
3. Genetic models et al., 2003; Hinkle et al., 2012)
In recent years, genetic models have been developed by manipu-

lating genes to create mutations that are causally linked to PD’s familial 3.1. α-Synuclein
cases (Fig. 2) (Kin et al., 2019). However, PD is mainly a sporadic dis-
ease; genetic mutations contribute only 10% of total PD cases (Kalinderi α-Synuclein, a protein expressed in presynaptic terminals of neurons,
et al., 2016). Moreover, transgenic models have shown quite different regulates membrane protein interactions and vesicle trafficking. The
pathological mechanisms and behavioral phenotypes than human PD. SNCA gene encodes α-synuclein and its mutation causes Park1, a familial
For example, these animal models failed to show a significant loss of form of PD with dominant inheritance. Familial PD is associated with
dopaminergic neurons, the main pathological signature of PD (Goldberg three α-synuclein point mutations: A30P, A53T, and E46K (Goedert
et al., 2017). Multiplication of the gene can induce PD, implying that the
Fig. 2. Schematic representation of experimental models of PD. (A) Toxin-induced models of PD; Various neurotoxins and their mechanisms in induction of key
clinical features of the disease. (B) Cellular models of PD; Existing approaches to model PD using co-cultures and iPSC-derived neurons/brain organoids. Future
prospects include integrating organoids (gut & brain organoids) into an assembloid system. The organ-on-chip system (magnified view depicts the layout) uses a
sophisticated fluidics system to establish a connection between two on-chip organs. (C) Genetic models of PD; Genetic mutation in α-synuclein, LRRK2, DJ-1,
PARKIN, and PINK1 leads to mitochondrial dysfunction and an increase in oxidative stress resulting in misfolding of protein to form LBs, neuroinflammation,
and neuronal cell death. (D) Artificial-induced models of PD; Machine learning uses complex powerful algorithm models (artificial neural network (ANN), decision
tree, K-nearest neighbor) to investigate the available data to identify patterns and predict biological outcomes to diagnose, detect severity, and analyze PD
progression.
7
amount of protein expression is also a contributing factor to the illness 3.2. Leucine-rich repeat kinase 2
(Ahn et al., 2008; Lee and Trojanowski, 2006; Vekrellis et al., 2011).
Various α-synuclein overexpressing transgenic mice models have been A dominant mutation in the LRRK2 gene causes late-onset autosomal
developed with distinct promoters and transgenes to recapitulate PD’s familial PD (Gandhi et al., 2009). The LRRK2 gene has been related to
pathogenesis. These models mimic only some aspects of pathogenesis, several point mutations, the most prevalent ones are G2019S (mutation
but not the entire spectrum of the disease. α-synuclein expression levels in the kinase domain) and R1441C (mutation in the guanosine
in the model are used to evaluate disease effects (Chung et al., 2019; triphosphate domain) (Table 2) (Mata et al., 2006; Smith et al., 2006;
Fernagut and Chesselet, 2004; Magen and Chesselet, 2010). α-synuclein Tsika and Moore, 2013; Zimprich et al., 2004). Several lines of LRRK2
overexpression in wild-type mice results in reduced olfactory function, knockout mice, transgenic mice overexpressing human wild-type, and
autonomic dysregulation, α-synuclein accumulation, and early motor the G2019S mutant LRRK2 have been developed (Volpicelli-Daley et al.,
deficits, but did not show nigrostriatal neuronal loss. Furthermore, re- 2016). Overexpression of LRRK2 disrupts the morphology and function
sults suggest that α-synuclein overexpression can induce multiple of the Golgi apparatus, thus increasing the neurological anomalies and
non-motor symptoms without causing dopaminergic neuro- pathogenic α-synuclein deposition in A53T α-synuclein transgenic mice.
degeneration. In contrast, mice lacking α-synuclein are alive, exhibit In contrast, these alterations are found to be diminished in LRRK2
lower DA levels in striatum, and exhibit reduced rearing. However, knockout mice (Lin et al., 2009). Elevated DA release in the striatum was
α-synuclein overexpressing mice display lower striatal DA levels and observed in transgenic mice overexpressing wild-type LRRK2 which
develop intraneuronal inclusions, despite lacking nigral cell death caused motor hyperactivity. In contrast, overexpression of mutant
(Chesselet et al., 2008; Fleming et al., 2008). The nigrostriatal dopa- LRRK2-G2019S mice showed a decrease in striatal DA, thereby sug-
minergic neurons are specifically lost in mice that overexpress a gesting a role of LRRK2 in DA transmission (Li et al., 2009).
double-mutated version of α-synuclein under the Tyrosine hydroxylase Age-dependent motor deficits in mice overexpress mutant LRRK2
(TH)-promoter. These studies used α-synuclein variants such as A30P R1441G, a gene associated with PD. These mice show progressive aki-
and A53T that had not been investigated in humans (Thiruchelvam nesia, a cardinal symptom of PD, which can be reversed by
et al., 2004). However, A53T mutation linkage to PD is not evaluated in anti-parkinsonian drugs such as levodopa and apomorphine. In contrast,
the murine model. The A53T mutation causes PD in humans and is mice overexpressing wild-type or G2019S LRRK2 do not exhibit signif-
described as being more lethal on a backdrop of α-synuclein-knockout icant motor impairments or neuronal loss, despite mild neuro-
mice than on a background of wild-type murine mice (Cabin et al., degeneration. These findings suggest that LRRK2 R1441G mutation
2005). α-Synuclein overexpression in TH promoter-controlled mice causes selective vulnerability to motor dysfunction and neuro-
leads to increased microglial activation in the substantia nigra, a hall- degeneration in a PD mouse model. However, mice expressing human
mark of neuroinflammation in PD. Moreover, neurochemical and gene BAC LRRK2 showed impaired DA release and uptake in the striatum.
expression analyses in these mice revealed that α-synuclein modulates Studies have reported that there is a significant reduction in the number
DA metabolism in the nigrostriatal pathway (Su et al., 2008; Yu et al., and survival of newborn neurons in the subventricular zone and olfac-
2008). tory bulb of mice overexpressing human G2019S LRRK2, compared to
Mouse model of overexpressed α-synuclein regulated by platelet- wild-type controls. Overall, LRRK2 mice models analyze cellular dy-
derived growth factor (PDGF) was created to simulate the pathophysi- namics involved in the degeneration of the nigrostriatal DA neurons in
ology of α-synuclein distribution in humans. Molecular analysis in the pathology of PD (Dawson et al., 2010; Kumar and Cookson, 2011;
PDGF-β α-synuclein overexpressing mice suggests that interaction be- Rui et al., 2018). However, few studies displayed that DA neurons may
tween phosphorylated fatty acids and cholesterol speeds up α-synuclein resist LRRK2 toxicity, possibly due to compensatory mechanisms pre-
accumulation. These observations are verified with the use of choles- venting their loss. Moreover, human LRRK2 mutations exhibit partial
terol synthesis inhibiter lovastatin which ameliorates later alteration penetrance, suggesting that additional genetic or environmental factors
(Koob et al., 2010; Masliah et al., 2000; Sharon et al., 2003). Prion are necessary for DA neurodegeneration. Inspite of these limitations
protein promoter overexpressing α-synuclein was used to investigate the different LRRK2 models could be useful tools in testing the novel neu-
effect of excess α-synuclein expression in neurons, mainly of substantia roprotective agents as therapy for PD (Xiong et al., 2017).
nigra in PD. Recent data suggests that Thy-1 promoter in C57BL/6 mice
showed widespread α-synuclein expression in neurons without causing
any motor deficits. Most studies have shown PD characteristics such as 3.3. PARKIN gene model
nigrostriatal DA loss with motor and non-motor impairments (Fleming
et al., 2004; Ikeda et al., 2009; Rockenstein et al., 2002). A mouse model Parkin is a 465-residue E3 ubiquitin ligase that mediates the ubiq-
was developed that overexpresses α-synuclein under the control of a uitination of proteins in the ubiquitin-proteasome system. PARKIN has a
calcium/calmodulin-dependent protein kinase IIa (CaM) promotor in role in preserving mitochondrial homeostasis; its loss of activity may
the olfactory bulb and hippocampus. It is employed to create treatments result in mitochondrial malfunction, which leads to the development of
that control the expression of α-synuclein in the early stages of the PD (Dawson and Dawson, 2010; Tanaka, 2010; Zhang et al., 2000).
illness. Although α-synuclein has been used in a large number of models, Mutations in the PARKIN gene cause early-onset autosomal recessive
its precise role remains elusive. Available data points to the possibility PD. PARKIN knockout transgenic mice lines are generated by deletion of
that α-synuclein functions as a presynaptic regulator of DA release, exon 3, 7, or 2 in the PARKIN gene. PARKIN exon’s three transgenic mice
synthesis, or storage (Lim et al., 2010; Marxreiter et al., 2009). Despite lines show early signs of PD, such as mitochondrial damage, a significant
several advantages α-synuclein also offers a few limitations. It is found in decrease in DA release, increased oxidative stress, and synaptic abnor-
numerous tissues, and can move back and forth between the blood- malities. However, none of these models exhibit dopaminergic neuronal
stream and the brain, making it challenging to determine if changes in loss in SNpc, highlighting a limitation in their utility as PD models.
its levels in bodily fluids accurately reflect PD pathology in the brain. PARKIN exon 7 null transgenic mice lines show catecholaminergic
Furthermore, α-synuclein comes in various forms—monomeric, oligo- neuronal loss in locus coeruleus and low levels of epinephrine in spinal
meric, and post-translationally modified—increasing the complexity of cord and olfactory bulb but no change in density of DA neurons in SNpc.
measuring this protein and understanding its role in PD (Ganguly et al., PARKIN-Q311X mutation causes significant toxicity to dopaminergic
2021). The misfolding and aggregation of α-synuclein can also lead to neurons in the SNpc. The mutation contributes to α-synuclein pathology,
various disruptions, including mitochondrial dysfunction, endoplasmic progressive nigrostriatal dopaminergic cell loss, and motor dysfunctions
reticulum (ER) stress, hindered protein clearance, membrane distur- (Goldberg et al., 2003; Palacino et al., 2004; Perez and Palmiter, 2005a;
bances, and synaptic dysfunction (Gómez-Benito et al., 2020). Periquet et al., 2005; Von Coelln et al., 2004).
8
Table-2
Genetic models of PD.
MODEL ANIMALS MECHENISM ADVANTAGES DISADVANTAGES REFRENCES
USED
α-Synuclein Rat, Mice, Three-point mutations of α-synuclein Pharmacological evaluation of No dopaminergic (Goedert et al., 2017;
Zebrafish, C (A30P, A53T, and E46K), α-synuclein therapies designed to protect neurodegeneration and cell Recasens and Dehay,
eligans positive intraneuronal inclusions, dopaminergic cells loss in SNpc. 2014)
degenerate of TH+ neurons
LRRK2 Mice, Point mutations (G2019S and R1441C) Evaluate the role of LRRK2 gene in Nuclear abnormalities, lack of (Hisahara and
Drosophila linked to PD, impairs the structure and PD pathology, induces α-synuclein aggregates and Shimohama, 2011;
function of Golgi complex, results in dopaminergic neurodegeneration formation of LBs Rudenko and Cookson,
selective and progressive 2014; Tsika and Moore,
neurodegeneration, 2013; Zimprich et al.,
2004)
PARKIN Mice, Mutation results in mitochondrial An integral part of the ubiquitin- No reproducible DA-related (Dawson and Dawson,
Drosophila, C damage, oxidative stress, impaired DA proteasome system, involved in abnormalities 2010; Narendra et al.,
eligans and NE release, synaptic abnormalities, maintaining mitochondrial 2010; Perez and Palmiter,
and dose-dependent dopaminergic cell homeostasis. 2005; Periquet et al.,
loss. 2005)
DJ-1 Mice, Recessive PD is caused by a mutation in Loss of neurons in VTA, no Additional evaluation (Goldberg et al., 2005;
Drosophila, C the DJ-1 gene. Down-regulation of DJ-1 unilateral loss of DA neurons in procedures are required to Rousseaux et al., 2012;
eligans has been observed to increase the SNpc validate this model Yokota et al., 2003)
susceptibility to oxidative stress and
proteasome inhibition.
PINK1 Mice, Mutation in PARK6 locus results in No abnormalities in DA neurons, LB formation and (Barazzuol et al., 2020;
Drosophila striatal dopaminergic loss of DA neurodegeneration not Lazarou et al., 2013;
neurodegeneration, deleted levels of DA detected Oliveras-Salvá et al., 2014)
and increased α-synuclein
phosphorylation
Nurr1 Mice knockout mice strains resulted in Progressive loss of neurons No LB formation (Jankovic et al., 2005;
progressive loss of striatal DA, loss of Kadkhodaei et al., 2009)
midbrain DA neuron markers, and
neuronal loss.
Pitx3 Mice knockout aphakia mice show complete Helps in studying age-dependent No α-synuclein aggregation (Hwang et al., 2005, 2009;
loss of dopaminergic neurons in SNpc, progressive loss of dopaminergic does not mimics the complete Wang et al., 2021)
impaired locomotion neurons and changes in locomotor pathophysiology of PD, needs
phenotype further investigations
VMAT2 Mice Knockout mice demonstrate Useful in studying role of vesicular Do not represent a clear (Fukui et al., 2007; Jiang
significantly reduced levels of DA, L- storage of monoamines and its picture of PD, not much et al., 2020; Taylor et al.,
DOPA-responsive motor deficits, effect on neurodegeneration and explored 2009)
α-synuclein accumulation, and the motor and non-motor
dopaminergic cell loss in SNpc. symptoms of PD
MitoPark Mice Dopaminergic neurodegeneration, Helpful in studying the loss of Not mimic the entire (Ekstrand and Galter,
Mouse impaired locomotion, intraneuronal dopaminergic neurons on pathogenesis of the disease, 2009; Galter et al., 2010;
inclusions locomotion, gait, tremors and not much investigated to Ricke et al., 2020)
rigidity validate the pathogenesis
NFκB/c-Rel- Mice Mice deficient of the c-Rel factor Motor deficits similar to PD Not yet extensively (Parrella et al., 2019,
Deficient exhibited a marked immunoreactivity hypokinesia investigated 2022; Pizzi and Spano,
Mice for fibrillary α-synuclein in the SNpc, 2006)
increased microglial reactivity in basal
ganglia, impaired locomotion
3.4. DJ-1 gene model research and are unsuitable for testing neuroprotective agents (Beal
et al., 2010)
DJ-1 is a cytoplasmic and mitochondrial molecular chaperone that
inhibits α-synuclein aggregation, a key pathological feature of PD. Loss-
3.5. PINK1
of-function mutations in DJ-1 cause autosomal recessive early-onset PD.
Moreover, DJ-1 deficiency increases susceptibility to oxidative stress
PINK1, a mitochondrial kinase, regulates Parkin-mediated mitoph-
and proteasome impairment, two major factors contributing to PD
agy by recruiting Parkin from the cytosol to the mitochondria and
pathogenesis (Hedrich et al., 2004; Shendelman et al., 2004; Yokota
enhancing its ubiquitination activity leading to their degradation by the
et al., 2003; Zhang et al., 2005). DJ-1 deficient mice also show increased
proteasome and the clearance of damaged mitochondria (Lazarou et al.,
sensitivity to neurotoxins, such as MPTP, suggesting that DJ-1 over-
2013). Early-onset autosomal PD is caused by a mutation in the PARK6
expression is probably a suitable defense against oxidative stress
locus of PINK1. Mild deficits of mitochondria and nigral neurotrans-
(Paterna et al., 2007). DJ-1 knockout mice (KO) models were generated
mission with greater susceptibility to ROS and oxidative stress were seen
by either deleting exon 2 or inserting a premature stop codon in exon 1
in PINK1 Knock out mice (Kim et al., 2005; Kitada et al., 2007). PINK1
of the DJ-1 gene. These models showed increased susceptibility to
KO overexpressing mice exhibit increased α-synuclein levels resulting in
neurotoxins and oxidative stress. DJ-1 KO mice displayed reduced
DA loss, but no neurodegeneration in the SNpc was observed. Transgenic
numbers of DA neurons in the SNpc, but no changes in DA levels. In
PINK1 KO rats developed recently exhibit DA loss, and motor impair-
contrast, DJ1-C57 mice, which express a human DJ-1 mutation, showed
ment mimicking PD signs and symptoms (Dave et al., 2014;
age-dependent degeneration of DA neurons in the SNpc and impairment
Oliveras-Salvá et al., 2013). In PINK1 null mice progressive depletion of
of the nigrostriatal pathway, leading to mild motor deficits (Goldberg
striatal DA is done by deleting 4–5 exon without affecting the SNpc.
et al., 2005; Kim et al., 2005). Due to the limited dopaminergic neuron
Furthermore, recent studies have shown that PINK1-mediated mitoph-
loss, DJ-1-deficient mouse models have limited usefulness beyond basic
agy, ER-mitochondria association and calcium signaling are involved in
9
PD pathology (Barazzuol et al., 2020). PINK1 knockout models do not activity as well as several gait-related deficiencies that resembled bra-
exhibit LB-related pathology, mirroring the mild LB-related pathology dykinesia and muscle rigidity (Baiguera et al., 2012). However, these
observed in autopsy results from PD patients with the PINK1 mutation models often necessitate multiple breeding crosses to achieve condi-
(Kin et al., 2019). tional deletion in adult mice, which may pose a logistical challenge
(Dovonou et al., 2023).
4. Other genetic models
5. Non-mammalian genetic models of PD
4.1. Nurr1-and Pitx3-gene knockout model
5.1. Drosophila
Transcription factors Nurr1 and Pitx3 are involved in the develop-
ment and regulation of the nigrostriatal system. The pitx-3 KO aphakia Drosophila melanogaster, a fruit fly, has recently come to light as a
mice show complete loss of dopaminergic neurons in SNpc (Jankovic unique genetic model for exploring PD-related pathogenic processes. By
et al., 2005; Lin et al., 2009). However, pitx-3 KO do not reproduce adopting the yeast protein GAL4/upstream activation sequence system
progressive degeneration of dopaminergic neurons as in PD. Generally, in combination with neuronal overexpression of wild-type or mutant
it is used to validate DA deficits in neurobehavioral tests in mice. Studies human synuclein (A53T or A50P), the first transgenic Drosophila fly lines
have shown that the expression of DAT and VMAT genes linked with a replicating the PD phenotype were developed. In this paradigm, trans-
high risk of PD could be regulated by Pitx3 (Hwang et al., 2005, 2009; genic flies overexpressing human synuclein (A53T or A50P) exhibit
Wang et al., 2021). Nurr 1 deficiency in Nurr1 KO mice strains results in pronounced age-dependent loss of dorsomedial dopaminergic neurons,
progressive loss of striatal DA, loss of midbrain DA neuron markers, and fibrillary inclusions containing synuclein, and motor impairment, which
neurodegeneration (Kadkhodaei et al., 2009). are restored by L-DOPA or DA agonists used to treat PD in people (Feany
and Bender, 2000). A research group showed that early soluble oligomer
4.2. VMAT2-knockout models variants of α-synuclein are linked to increased dopaminergic degenera-
tion in Drosophila. Except α-synuclein, most of the genes linked to PD
VMAT2 is involved in the vesicular storage of monoamines, partic- have fly homologues. Mutations causing loss-of-function or dopami-
ularly DA, NE, and 5-HT. VMAT2 deficient mice with reduced expression nergic neuron-specific inactivation of fly homologues of PINK1, Parkin,
of VMAT2 demonstrate significantly reduced levels of DA due to pro- DJ-1, LRRK2, and HtrA2 can mimic PD-like loss of dopaminergic neu-
gressive loss of dopaminergic neurons, L-DOPA-responsive motor and rons and locomotor deficits (Imai et al., 2008; Sang et al., 2007; Tain
non-motor deficits, α-synuclein accumulation, and dopaminergic cell et al., 2009; Whitworth et al., 2008; Yang et al., 2008). However, ho-
loss in ventral tegmental area/substantia nigra and striatum (Jiang mologue gene loss in Drosophila causes weaker phenotypic alteration
et al., 2020; Taylor et al., 2009, 2011). Moreover, VMAT2-deficient than familial PD in humans with no LB formation, thought to be because
mouse model also presents progressive deficits in olfactory discrimina- of the absence of α-synuclein homologue. Studies have shown that
tion, delayed gastric emptying, altered sleep latency, anxiety-like overexpression of LRRK2-G2019S results in hep or JNKK-mediated se-
behavior, and age-dependent depressive behavior (Fukui et al., 2007; lective degeneration of dopaminergic neurons and retinal necrosis leads
Taylor et al., 2009). to reduced life span (Yang et al., 2018). Parkin and PINK1 null
Drosophila mutants showed early mortality, mitochondrial dysfunction,
4.3. MitoPark mouse and degeneration of flight muscles that cause climbing and flight dis-
abilities. However, overexpression of PINK1 in the fly leads to the
The MitoPark mouse has been developed through the elimination of amelioration of these α-synuclein dependent molecular and behavioral
the mitochondrial transcription factor A (TFAM) gene resulting in the phenotypes. Drosophila expresses two DJ-1 homologues like mammals:
disruption of mitochondrial function in the dopaminergic neurons DJ-1α and DJ-1β. Mutation in DJ-1β KO flies leads to increased sus-
(Ekstrand and Galter, 2009). These mice survive to the adult stage and ceptibility to cytotoxins, such as paraquat, H2O2, and rotenone, and ROS
show PD phenotype, including progressive degeneration of nigrostriatal accumulation in the fly brain (Hirth, 2010; Karpinar et al., 2009).
dopaminergic neurons, and reduced striatal DA accompanied by the Limitations of Drosophila as model organism include no suitability for
formation of intraneuronal inclusions or LB in dopaminergic neurons. biochemical studies requiring abundant and uniform tissue samples due
MitoPark mice do not reflect specific PD-related mutations, but it re- to their small size. Additionally, lack of an adaptive immune system
capitulates alteration in cellular pathways known to be affected in PD limits their suitability for studying certain aspects of PD pathophysi-
(Ekstrand et al., 2007; Galter et al., 2010; Ricke et al., 2020). ology. Another significant drawback is the absence of a counterpart of
the SNCA gene, responsible for encoding α-synuclein, resulting in a lack
4.4. NFκB/c-Rel-deficient mice of endogenous LB pathology in these flies (Nagoshi et al., 2018).
The nuclear factor κβ/c-Rel regulates the expression of pro-survival 5.2. Caenorhabditis elegans
manganese superoxide dismutase (MnSOD) and Bcl-xL genes involved
in increasing neuronal resilience to pathological noxae (Chen et al., Caenorhabditis elegans (C. elegans) is a simple multicellular organism
2000; Pizzi and Spano, 2006). The SNpc of mice lacking the c-Rel factor with primitive nervous system and well-characterized genome. It has
showed prominent immunoreactivity for fibrillary α-synuclein, as well emerged as a useful model for genomic studies as it is prone to genetic
as elevated expression of divalent metal transporter-1(DMT1) and iron manipulations. Strains can be cryopreserved without losing viability,
staining in the SNpc and striatum and develops sporadic PD-like enabling long-term storage of different strains. It has a simple nervous
phenotype (Parrella et al., 2019, 2022). In 2-month-old young c-rel− /− system with only 302 neurons, including eight dopaminergic ones that
mice prodromal symptoms (constipation and hyposmia) were reported. are affected in PD. It also possesses orthologues of most human PD
Since age of 5 months the c-rel− /− mice exhibit initiation of α-synuclein genes, such as Parkin, LRRK2, PINK1, and DJ-1, except for α-synuclein.
deposition from locus coeruleus, dorsal motor nucleus of the vagus and Overexpression of human α-synuclein mutants (A53T, A30P) causes
olfactory bulbs, which further at 12 months age involves the SNpc. In the dopaminergic neuron loss and phosphorylated α-synuclein aggregation
basal ganglia of 18-month-old c-rel/mice brains, there has been an in- in cell bodies and dendrites (Karpinar et al., 2009). Parkin KO C. elegans
crease in microglial reactivity but no astrocytic response (Parrella et al., with mutation in the Parkin gene produce and accumulate a truncated
2019; Porrini et al., 2017). Additionally, during a catwalk study, protein showing increased sensitivity to mitochondrial inhibitors and
c-rel/mice displayed age-dependent deficits in locomotor and total hypersensitivity to stress in the ER. In addition, C. elegans mutants for
10
DJ-1 and PINK1, also display enhanced sensitivity to PD-inducing Various types of cultures, including mesencephalic slice cultures and
toxins. The LRKK2 overexpression in G2019S mutant C. elegans exac- dopaminergic neuron cell lines, are utilized with different conditions.
erbated dopaminergic neuron loss, resulting in a decline in DA levels and These diverse conditions and outcome parameters significantly influ-
increased sensitivity to rotenone, whereas overexpression of wild-type ence experimental results and subsequent conclusions. Furthermore,
LRKK2 conferred protection against rotenone-induced toxicity these models fail to provide pharmacokinetic and behavioral aspect of
(Springer et al., 2005; Ved et al., 2005). Key limitations of utilizing the disease (Falkenburger and Schulz, 2006).
C. elegans for PD research include the absence of α-synuclein counter- In recent years, SH-SY5Y, PC12 and Lund human mesencephalic
part, difficulty in conducting molecular targeting of DA neurons (which (LUHMES) cell lines have been extensively used in neurological research
represent only a small fraction of total cells), and variations in neuronal (Nagamura et al., 2014; Smirnova et al., 2016; Xicoy et al., 2017).
connectivity compared to humans (Cooper and Van Raamsdonk, 2018). SH-SY5Y cell lines multiply rapidly, are easy to culture and dopami-
nergic cell generation from these lines is very fast. These cell lines are
5.3. Zebrafish obtained from human subjects containing various human-specific pro-
teins. SH-SY5Y cell lines are widely used to study MPTP-induced
Zebrafish models are exciting novel models used to evaluate PD neuronal toxicity, 6-OHDA-induced cellular apoptosis, α-synuclein ag-
pathogenesis because they produce large numbers of transparent em- gregation and mitochondrial fragmentation (Eum et al., 2019; Yiğit
bryos, develop rapidly, and are prone to genetic manipulation. Zebrafish et al., 2018). These cell lines imitate impaired dopaminergic neurons
brains are simplified versions of mammalian brains, making them and similar to dopaminergic neurons are sensitive to oxidative stress
excellent model systems for investigating neurological disorders and (Table 3). However, SH-SY5Y cell lines are not considered as authentic
developing high-throughput drug screening. Similar to Drosophila and dopaminergic cell lines (Gong et al., 2017; Yiğit et al., 2018). The PC12
C. elegans, dopaminergic neurons (14 in total) of zebrafish are vulner- cell lines are sensitive to 6-OHDA, MPP+, paraquat and
able to PD-inducing toxins. Genome-wide studies detected PD-related rotenone-induced toxicity. These cell lines grow, multiply, synthesize,
gene homologues such as PINK1, LRKK2, and DJ-1except gene homo- store and are even stimulated to release DA and NE (Zhang et al., 2016,
logue to human α-synuclein. Parkin KO in fish causes degeneration of DA 2017; Zhou et al., 2017). PC12 cells were reported to be beneficial in
neurons, decreased complex-1 activity, and enhanced vulnerability to studying the role of iron accumulation in SNpc of PD patients as iron
PD-inducing toxins (Fett et al., 2010; Sheng et al., 2010). However, there accumulation causes oxidative stress and neurodegeneration in SNpc
is no marked DA neuron loss in DJ-1 KO fish embryos, but it induces reported in PD (Fernández et al., 2017). LUHMES cells derived from
enhanced neuronal sensitivity towards PD-inducing toxins. Similarly, mesencephalic tissue of human fetus shows dopaminergic phenotype on
knocking of the PINK1 gene in zebrafish causes alteration in dopami- differentiation and high sensitivity to MPP+ with elevated TH levels
nergic projections and motor deficit without dopaminergic neuron loss (Smirnova et al., 2016; Zhang et al., 2014). The astrocytes co-culture
(Bretaud et al., 2007; Xi et al., 2010). However, PINK1 point mutations with LUHMES approach is used by many researchers to explore the
cause a loss of dopaminergic neurons and mitochondrial function due to neuroprotective effects of astrocytes (Efremova et al., 2015). Novel cell
loss of the kinase domain at the larval stage. Thus suggests that the cultures using microfluidics allow imaging of movement of organelles
Zebrafish model could be a potential tool for high-throughput testing and α-synuclein transport through neurite (Bieri et al., 2018). Other
and screening of novel therapeutic molecules to treat PD (Xi et al., catecholaminergic cell lines such as, RCSN-3, N27, MEs23.5, MN9D and
2011). However, Zebrafish as model organism offers several disadvan- CAD cell lines expressing dopaminergic features such as DA transport,
tages in evaluation of PD pathology and drug efficacy. Firstly, reuptake, formation of neuromelanin, release of DA, and monoamine oxidase are
metabolism, and excretion of different drug molecules vary in each extensively utilized to study selective loss of dopaminergic neurons in
zebrafish and is very different from humans leading to heterogeneity in SNpc. RCSN-3 cell line is obtained from the substantia nigra region of
results (Chia et al., 2022; Saleem and Kannan, 2018). Secondly, Zebra- adult rats and releases enzymes responsible for catecholaminergic
fish have the innate ability to repair damaged or dead cells through functions. A study confirmed its role in the synthesis and release of DA
neurogenesis and regeneration (Barbosa and Ninkovic, 2016; Godoy without the need for expensive and lengthy differentiation procedures,
et al., 2020). Lastly, humans, have two MAO subtypes (MAO-A and proving its advantages over PC12 and SH-SY5Y cell lines. It also ex-
MAO-B), zebrafish possess only one MAO type, known as the zMAO presses α-synuclein, mRNA for glutathione peroxidase, and DA receptor
which is hypothetically considered as similar to MAO-A as no known D1 and D5. The cells produce neuromelanin during the proliferation
protein structure of zMAO is available. Since, MAO is very essential due phase aiding in the study of neurodegeneration in melanin-containing
to its implication in PD pathology (Angelica et al., 2013), these un- dopaminergic neurons in PD (Paris et al., 2008). N27 cell line is
certainties might make it more difficult to translate study results into derived from a rat fetus and produces DA and its metabolites (Segur-
clinically useable techniques. a-Aguilar, 2011). The original cell line’s subjection to multiple passages
led to the development of a mixture of cell types with variability in their
6. Emerging in-vitro models tyrosine hydroxylase expression. A series of clonal cultures were con-
ducted to obtain N27-A cells with a high expression of tyrosine hy-
6.1. Cellular models droxylase. N27-A cells portray a higher sensitivity to MPP+ and 6-OHDA
as compared to N27 cells and showcase DA release when given a basal
PD has complex pathological mechanisms during its development and depolarized environment. This cell, thus, exhibits potential as an
and progression. The current animal model fails to replicate all PD improved model for PD research (Gao et al., 2016). Furthermore,
pathological features (Potashkin et al., 2011). The cellular models give MEs23.5 is a hybrid cell lines resulting from N18TG2
an edge in easy gene alterations and in avoiding ethical concerns related neuroblastoma-glioblastoma and mesencephalic rat cell lines. It mani-
to mammalian models. Cellular models are advantageous as large fests dopaminergic characteristics akin to substantia nigra origin
number of cultures can be produced that can be sufficient to study alongside the expression of tyrosine hydroxylase. In research, MEs23.5
α-synuclein aggregation pathology, oxidative stress, apoptosis and spe- serves as a valuable model for drug evaluation, with widely used com-
cific gene manipulation effects. These models allow rapid screening of pounds such as MPTP, 6-OHDA, and rotenone applied to induce specific
therapeutic agents and limit animal experiments (Lázaro et al., 2017). cellular phenotypes for experimental purposes (Ke et al., 2021). Similar
Cell cultures in PD also present limitations due to factors such as the to MEs23.5, MN9D is also a hybrid cell line originating from N18TG2
dependence of neuron survival on culture conditions and the lack of and rostral mesencephalic tegmentum which in addition to expressing
natural neuronal network development. Most neurons are isolated from tyrosine hydroxylase, is involved in the synthesis, release and uptake of
their physiological connections, impacting the relevance of findings. DA. In addition, it can differentiate into cells with features associated
11
Table 3
Emerging cellular, organoid, organ-on-chip models and AI-based models of PD.
S. MODEL Animals used MECHENISM ADVANTAGES DISADVANTAGES REFRENCES
No
1. SH-SY5Y Human Allows generating a large number Human-specific proteins present Not authentic dopaminergic (Colapinto et al.,
neuroblastoma of dopaminergic cells, impaired can be investigated, cells are neuronal cells 2006; Gong et al.,
DA levels imitate with the easy to culture and multiply, 2017; Xie et al.,
transporters (DAT and VMAT). large percentage of cells 2010)
2. PC12 cells Human Synthesize and release Effective sympathetic neuronal Cell culture and maintenance (Fernández et al.,
neuroblastoma catecholamines (DA and NE), model useful in investigating are highly expensive 2017; McAllum and
sensitivity towards neurotoxins neurons affected in PD, useful in Finkelstein, 2016;
with 6-OHDA, MPTP, rotenone, exploring iron accumulation and Zhou et al., 2017)
paraquat its implications on SNpc in PD
patients
3. LUHMES Human Exerts α-synuclein mediated Robust dopaminergic Difficult and less efficient to (Rutherford et al.,
neuroblastoma cytotoxicity phenotype, Susceptible to MPP+ transfect 2014; Smirnova
cytotoxicity, High TH levels et al., 2016; Zhang
et al., 2014)
4. iPSC Human Containing the SNCA triplication Large number of cells can be isolated from PD patients, (Byers et al., 2011;
neuroblastoma was used to generate DA neurons, generated mimicking the PD batch-to-batch variation Ryan et al., 2013;
these cells lack dopaminergic microenvironment, patient- among patient lines and even Woodard et al., 2014;
neuronal phenotype, show derived iPSC-DA neurons exhibit within identical clonal Zhang et al., 2017)
slowed neurite growth, and multiple pathogenic phenotypes populations from same
disrupted electrophysiological in PD, useful in studying role of patient, Cultures are
action. aging in long-term cultures extremely costly
5. RCSN-3 Substantia nigra of Synthesize and release DA, Produce neuromelanin during Not yet extensively Paris et al. (2008)
adult rats expresses α-synuclein, mRNA for the proliferation phase aiding in investigated
glutathione peroxidase, and DA the study of neurodegeneration
receptors D1 and D5. in melanin-containing
dopaminergic neurons in PD
6. N27 Rat fetus Produces DA and its metabolites Contains basal levels of multiple N27-A cells display a higher (Segura-Aguilar,
dopaminergic markers and is an sensitivity to MPP+ and 6- 2011; Gao et al.,
immortalized cell line. OHDA as compared to N27 2016; Cagle et al.,
cells and showcase DA release 2021)
when given a basal and
depolarized environment
7. MEs23.5 N18TG2 Produces characteristics similar Serves as a valuable model for Not yet extensively Ke et al. (2021)
neuroblastoma- to substantia nigra and causes drug evaluation with MPTP, 6- investigated
glioblastoma and expression of tyrosine OHDA, and rotenone applied to
mesencephalic rat hydroxylase induce specific cellular
cell lines phenotypes
8. MN9D N18TG2 and rostral Expresses tyrosine hydroxylase, Demonstrate DA uptake Are good DA reserves but are Ke et al. (2021)
mesencephalic rat involved in the synthesis, release, characteristics, differentiated incapable of its conversion
tegmentum and uptake of DA MN9D cells can serve as a model into NE, undifferentiated
for replicating the gradual MN9D cells are unsuitable for
degeneration of DA neurons. studying DA neurons.
9. CAD Mouse neurons Cause L-DOPA accumulation Allows study of neuronal Incapable of DA synthesis or (Arboleda et al.,
development since they have the secretion 2005; Li et al., 2007)
morphological and biochemical
properties of primary neurons.
10. Organotypic Transgenic or gene Models brain interactions to Offer a versatile platform for Brain slices from adult mice (Elfarrash and
Brain Slice knockout mice, study α-synuclein pathology in modifying alpha-synuclein have diminished neuronal Jensen, 2021; Uçar
cultures PD pathology, Allows precise viability. et al., 2022)
control over experimental
conditions.
11. Organoids Human isolated from idiopathic PD Provide an advanced patient- Slow maturity, lack of (Galet et al., 2020;
neuroblastoma patients and the individuals’ specific platform for in vitro complex interaction and Marotta et al., 2020;
harboring mutations in genes disease modeling vascularization, deficient Yeap et al., 2023)
(SNCA, LRRK2, PINK1, DNAJC6, nutrient supply, and low
GBA1and parkin) shows a analytical accessibility persist
decrease in TH levels and
α-synuclein aggregation and LB-
like inclusions indicative of
neurodegeneration
12. Organ-on-Chip Human iPSC derived from PINK1 mutant Microfluidic chip helps in Most organ chips are low (Leung et al., 2022;
neuroblastoma dopaminergic neurons cultured understanding long-term throughput, highly expensive, Sabate-Soler et al.,
using microfluidic devices, dynamic environment and not yet extensively explored 2022; Sozzi et al.,
microchips seeded with Aβ42 biochemical changes occurs in in 2022; Spitz et al.,
seeds shows amyloid aggregation. vivo systems in PD, helps in high 2022)
throughput screening of PD
pharmacotherapies.
13. Artificial Computational AI-based and ML techniques Early detection of severity and Bias investigation in AI (Belić et al., 2019;
intelligence tools, machine utilized to analyze breathing progression of PD as it builds a systems due to inadequate Dixit et al., 2023;
-based models learning algorithms patterns, movements of robust high potential decision- data collection or reporting, Yang et al., 2022)
extremities and data available on making network, high poor validation, no
online platforms to diagnose and throughput screening of PD transparency in choosing ML
identify neurodegenerative drugs. models
progression in PD
12
with dopaminergic neurons. MN9D cells are shown to be good DA re- (Fernández-Santiago et al., 2019; Hsieh et al., 2016; Tolosa et al., 2018).
serves but are incapable of its conversion into NE. Unlike undifferenti-
ated SH-SY5Y cells, MN9D cells demonstrate catecholamine uptake 6.2. Organotypic brain slice cultures
properties. Consequently, undifferentiated MN9D cells are unsuitable
for studying DA neurons. However, a deficiency of differentiated MN9D Organotypic brain slice culture is a technique that allows the growth
cells can serve as a model for replicating the gradual degeneration of DA of a living tissue in an in vitro system to preserve the architecture,
neurons in mechanistic investigations (Ke et al., 2021). In addition, physiology, and its interaction with surrounding tissues. It mimics in vivo
Cath.a-differentiated (CAD) cells obtained from mouse neurons are turn systems better than cell culture models making it useful for studying
out to important models for investigating catecholaminergic neuronal α-synuclein pathology in PD (Elfarrash et al., 2019; Elfarrash and Jen-
death (Arboleda et al., 2005). L-DOPA accumulation is a feature of CAD sen, 2021). The movement of α-synuclein aggregates in an anterograde
cells that proves their involvement in the DA transport mechanism. manner between different brain regions can be analyzed via brain slice
They, however, are incapable of secretion or synthesis associated with cultures post α-synuclein preformed fibrils (PFF) microinjection in a
DA. time-dependent manner, making them useful to study α-synuclein
Recently, pluripotent stem cells (iPSC) neurons models have gained expression in the brain. A study demonstrated this model’s use in
limelight as access to human neuronal tissue is very difficult and there is studying varying seeding abilities of different α-synuclein PFF poly-
an intricate difference between animal models and human pathologies morphs as well (Uçar et al., 2022). α-synuclein pathology suggests a role
(Burbulla et al., 2017; Gitler et al., 2017). The TGFβ induced neural fate of both astrocytes and microglia in spreading α-synuclein aggregates
through SMAD inhibition has led to development of protocols to followed by neurodegeneration. Slice cultures embed neurons in a glial
generate multiple populations of neuronal subtypes (dopaminergic, matrix that replicates this environment and its implications in contrib-
cortical, cholinergic, GABAergic, hippocampal, hypothalamic) and glial uting to PD for the effective study of PD pathophysiology. This essen-
cells (Chambers et al., 2009; Marotta et al., 2020). Dopaminergic neu- tially corroborates their use in addressing the impact of endogenous
rons derived from PD patients differentiated using SMAD inhibition α-synuclein on disease progression and fortifying the major aggregate
protocol proved insightful in PD pathology (Garcia-Leon et al., 2019). spreading pathology-anterograde versus retrograde. Slice cultures also
Human-iPSC-derived dopaminergic neuron culture developed from pa- offer a versatile platform for modifying alpha-synuclein pathology. By
tients having mutant A53T α-synuclein triplication helps to give insights utilizing slice cultures derived from transgenic or gene knockout mice,
in disrupted multiple pathways in PD patients (Ryan et al., 2013). or by employing viral expression vectors, researchers can readily
Human-iPSC-derived dopaminergic neurons were reported to have manipulate the expression of α -synuclein, its mutants, or other proteins
increased α-synuclein, oxidative stress, and oxidized DA levels (Byers of interest. Moreover, the use of knockout mice or small interfering RNA
et al., 2011; Devine et al., 2011). Furthermore, increased ER stress, (siRNA) techniques enables the targeted reduction of specific proteins,
impaired mitochondrial respiration, decreased neuronal growth and allowing for precise control over the experimental conditions and
activity in iPSC-derived cortical neurons harboring α-synuclein dupli- facilitating investigations into the modulation of α -synuclein pathology
cation (E46K and E57K) and triplication (Heman-Ackah et al.,; Oliveira (Elfarrash and Jensen, 2021).
et al., 2015; Prots et al., 2018). The human-iPSC-DA neurons harboring A major advantage these cultures exhibit is their ability to model
the LLRK2 (G2019S, R1441G and I2020T) mutation have been shown brain interactions, thus, implying their usefulness over studying single-
increased α-synuclein aggregation, oxidized DA and mitochondrial DNA brain areas (Uçar et al., 2022) allowing the study of the complex system
damage (Borgs et al., 2016; Fernández-Santiago et al., 2019; López de of α-synuclein spreading in the brain in a more convenient setting
Maturana et al., 2016; Ohta et al., 2013). In addition, some studies re- (Elfarrash and Jensen, 2021). A study conducted using brain slice cul-
ported reduced neurite growth, increased apoptosis, impaired NF-kB tures incubated the cultures for over 9 weeks, suggesting this model’s
signaling and impaired tau and tubulin phosphorylation (López de suitability for long-term studies associated with PD and aging (Uçar
Maturana et al., 2016; Nguyen et al., 2011; Sanders et al., 2014). et al., 2022). In ethical terms, they provide an alternative to animal
Human-iPSC DA neurons derived from PD patients having PINK1 studies by reducing the number of animals required for setting up a
(Q456X or V170G) mutation have shown impaired parkin recruitment study (Alaylioğlu et al., 2020; Moudio et al., 2022). However, the most
to mitochondria, mitochondrial dysfunction, and disrupted mitophagy commonly used brain slices i.e. from pups do not portray an adult brain,
(Puschmann et al., 2017; Seibler et al., 2011). Additionally, some studies which is the most probable place to study PD, rendering this its limita-
reported that iPSC DA neurons having parkin V324A mutation elevated tion; cultures from adult mice though possible, have diminished
levels of oxidized DA and disrupted DA release and uptake via DAT neuronal viability (Elfarrash and Jensen, 2021; Uçar et al., 2022). Be-
leading to impaired DA dynamics (Burbulla et al., 2017; Jiang et al., sides, they are unable to portray any systemic or behavioral mechanisms
2012; Ren et al., 2011). Mutation in GBA1 gene that encodes for glu- associated with PD, making them strong models but incomplete sub-
cocerebrosidase (GCase) causes Gaucher disease (GD), a lysosomal stitutes for in vivo studies (Alaylioğlu et al., 2020).
storage disorder (Neumann et al., 2009). Approx. 5–10% of PD patients
have GBA1 mutation. Mutant GBA iPSC-derived neurons from PD pa- 6.3. Neural organoids
tients display higher levels and accumulation of α-synuclein and lipids, a
major hallmark in these neurons (Aflaki et al., 2016; Kim et al., 2018; The advent of iPSC technology enables researchers to develop and
Schapira and neuroscience, 2015). Additionally, defective lysosome and establish 2D or 3D organoids which help to study spatial interaction
ER, mitochondrial dysfunction, and autophagic defects have been re- between diverse population of cells on a dish (Fig. 2), complex impaired
ported in several studies (Fernandes et al., 2016; Schöndorf et al., 2014). cross-talk mechanisms between cells and various omic changes in
Other genes involved in familial PD such as SJ-1, DJ-1, VPS35 and neurodegenerative disorders such as PD (Choudhury et al., 2022; Zagare
PARK9 have also been explored in different studies to understand et al., 2022). Neural organoids are 2D or 3D structures grown from
PD-pathology in patient-derived iPSC dopaminergic neurons (Bonifati pluripotent stem cells comprises of brain-specific cell types that
et al., 2003). self-organize to form ordered structure and cytoarchitecture (Kelava and
Development of human-derived iPSC DA neurons for the first time Lancaster, 2016). These organoids are having neuromelanin-like gran-
makes a possibility to model non-genetic forms of PD. The iPSC DA ules and the potential to form functional neuronal networks with
neurons isolated from idiopathic patients displayed impaired mito- increased neural maturity (Jo et al., 2016; Monzel et al., 2017). Several
chondrial respiration and oxidized DA and DJ-1 (Burbulla et al., 2017; research groups characterize the human midbrain organoids (hMOs)
Mazzulli et al., 2016). In addition, idiopathic DA neurons also show less isolated from idiopathic PD patients and the individuals’ harboring
GCase activity, DNA hyper methylation and microRNA alterations mutations in genes (SNCA, LRRK2, PINK1, DNAJC6, GBA1and parkin)
13
that recapitulate the features of PD. In addition, hMOs derived from reach clinics in real time and will aid PD patients.
idiopathic PD patients show a decrease in growth and TH levels indic-
ative of neurodegeneration. Moreover, elevated levels of 6.5. Artificial intelligence-based models
pentaxin-related protein (PTX3), a marker of disease severity was also
reported (Chlebanowska et al., 2020; Yeap et al., 2023). Another study Artificial intelligence (AI) or machine learning (ML) is an advancing
reported that hMOs carrying GBA1− /− and SNCA mutation displays TH+ field that has broad applications in many areas of healthcare (Jiang
DA neurons with higher α-synuclein aggregation, and most importantly et al., 2017). ML is a subset of AI that uses complex powerful algorithms
these organoids recapitulate LB- like inclusions, a hallmark of PD in in to run systems to investigate the available data to find patterns and
vitro systems (Jo et al., 2021). In recent study, hMOs comprising predict the expected outcome by the learning experience. AI and spe-
LRRK2-G2019S mutation mimic PD phenotypes in a system with less cifically ML brought applications in assessing and diagnosing cognitive
neuronal density and complexity. These organoids show elevated functions, neurodegenerative processes and intelligent behavior in
thiol-oxidoreductase (TXNIP) and FOXA2 during development which is humans (Hamet and Tremblay, 2017; Rovini et al., 2017). ML tech-
considered as compensatory response to counteract the defective spec- niques such as artificial neural network (ANN), naïve bayes, decision
ifications of mid-brain dopaminergic neurons caused by LRRK2-G2019S tree, K-nearest neighbor, K-mean clustering, random forest (Fig. 2),
mutation, suggesting the role of LRRK2 in neurodevelopment (Smits support vector machine and ensembled models are currently used to
et al., 2019; Uzquiano et al., 2022). Furthermore, the transcriptomics of diagnose, detect severity and progression of PD (Dixit et al., 2023). In a
these organoids revealed that DNAJC12 along with APP, GATA3 and recent study, a research group used an AI-based model system for the
PTN are considered main candidate genes involved in transcriptional detection and assessment of PD based on nocturnal breathing signals
changes during early neurodevelopmental stages in LRRK2-G2019S (Yang et al., 2022). Online available data describing motion of upper
mutant organoids, establishing the link to PD (Zagare et al., 2022). and lower extremities on PubMed and Science Direct with AI or ML tools
Together these findings pave the way to gain insights into what is wrong enables researchers to diagnose, perform therapy assessment and track
in the brain of PD patients. Majority of brain-derived organoids repre- treatment progress in PD patients (Belić et al., 2019). Furthermore,
sent a specific brain region which is devoid of vascularization. This AI-based computational tools and pharmacoepidemiology is used
becomes a limitation because it is well known that PD development and recently to discover and explore drugs that inhibit α-synuclein accu-
progression involves complex cross-talk between different population of mulation and has disease-modifying potential for PD (Maclagan et al.,
cells and regions of brain. This limitation could be resolved in near 2020). In summary, AI or ML-assisted diagnosis of the severity and
future with use of multisystem interaction models (Assembloids) to progression of PD is advantageous as it builds a robust high potential
understand brain pathophysiology during disease (Marton and Pasca, decision-making network, and exploration and adoption of novel bio-
2020). markers will result in early detection of PD. In near future, AI tools could
be combined with automated 2D or 3D organoid assembloids that help
6.4. Organ-on-a-chip models in building a new generation of interdisciplinary high-throughput
screens for PD (Renner et al., 2021). However, AI-based models offer
Organ-on-a-chip (OoC) systems are microfluidic devices that contain several limitations such as biased investigation in AI systems due to
human tissue engineered to recapitulate key aspects of organ function inadequate data collection or reporting, poor validation, and no trans-
and disease with specific microenvironments (Fig. 2) (Leung et al., parency in choosing ML models and how they are trained, thus blurring
2022). Several groups develop OoCs miniature system, a the original outcomes (Erro et al., 2016; Kwon et al., 2018; Paul et al.,
multi-organ-on-a-chip system under the European Research 2022). Furthermore, the lack of well-curated cohorts makes the process
Council-Funded ‘MINERVA’ project to access the impact of the intestinal of realigning and combining intricate multi-source and multi-site PD
flora on neurodegeneration (Kim et al., 2021; Raimondi et al., 2019). databases extremely difficult. Additional challenges include compre-
Recently a research group used microfluidic technology to evaluate hending the complexities of sound signal processing and building ma-
gut-liver-cerebral interaction in PD that are bathed in medium circu- chine learning models utilizing unclean public data. It is crucial to
lated culture medium containing immune-related CD4+ regulatory T explain how the experimental classification method is different from a
and Th17 cell. This miniature system helps to understand the role of diagnosis made by a neurologist and to offer insights into the behavior of
microbiota associated with short-chain-fatty acids (SCFAs) in the path- the model that go beyond performance metrics (Dixit et al., 2023).
ogenesis of PD (Trapecar et al., 2021). Thus, with use of OoCs technol-
ogy, gut compartment could be linked to brain assemblies to investigate 6.5.1. Future directions
the α-synuclein propagation from gut to brain and the authentic pre- In exploring PD, a single model may fall short of capturing its
diction of brain regions for α-synuclein transmission (Nashimoto et al., multifaceted nature. However, a multimodal approach holds promise in
2017). The major disadvantage with brain-derived organoids is lack of integrating diverse imaging biomarkers, elucidating neuroanatomical
vascularization which restricts their growth in in vitro systems and and pathophysiological mechanisms, and tracking disease progression.
promotes necrosis in core areas of organoids lacking proper oxygena- Transgenic and neurotoxic rodent models will remain a crucial part of
tion. To tackle the tissue necrosis issue researchers used co-culturing the translational approach toward precision therapy in PD. They make it
astrocytes and microglia to enhance neuronal viability in organoids easier to understand the underlying mechanism of the disease, find
(Sabate-Soler et al., 2022). A research group used spider silk microfibers biomarkers to diagnose and categorize PD patients and screen new
with laminin and carbon fibers and assembled a 3D scaffold that facil- therapeutics utilizing the appropriate model or combination of models
itated oxygen flow and metabolic waste removal to solve tissue necrosis before entering clinical trials (Simons and Fleming, 2023). Cellular
issue (Sozzi et al., 2022; Tejchman et al., 2020). A novel organ-on-a-chip models have been used for decades to duplicate PD pathogenesis in an in
platform that integrates multiple sensors to monitor the electrophysio- vitro system using cell lines from rodents (Ke et al., 2021). hPSCs,
logical, respiratory, and dopaminergic functions of human midbrain however, promise a realistic approach to PD by mimicking human
organoids was developed in a recent study. Microfluidic culturing cellular functioning with accuracy. Hypoimmunogenic hPSCs de-
improved tissue viability, differentiation, and clinical relevance by rivatives and cell transplantation therapy are under exploration for
reducing necrotic core formation (Spitz et al., 2022). Furthermore, it is treating PD by utilizing new techniques of reprogramming stem cells.
anticipated that in the future 3D brain structures that could mirror Although hPSCs pose a feasibility and safety risk, experiments are un-
human brain systems with fidelity and uncover the hidden brain-body derway to optimize the stem cell approach to enhance its safety and
interaction fuels the investigations regarding PD pathogenesis. At the efficiency (Cha et al., 2023). CSF biomarkers, on the other hand, show
same time high-throughput screening of novel PD therapeutics will potential in predicting PD before symptom emergence which will be
14
helpful in early disease diagnostics (Cassotta et al., 2022). editing. Shivam watts: Manuscript preparation. Kanwaljit Chopra:
While 3D organoids have yet to be extensively utilized in PD drug Conceptualization, Writing – original draft, Writing – review & editing.
screening, advancements in technology indicate their potential. Inno-
vative strategies addressing scalability and cost issues, such as engi-
neered microenvironments and brain-on-a-chip platforms, offer avenues Declaration of competing interest
for high-throughput drug discovery campaigns. These platforms,
equipped with miniaturized perfusion systems, enable long-term growth The authors declare that they have no known competing financial
and have the potential to drive fundamental discoveries and the devel- interests or personal relationships that could have appeared to influence
opment of more effective PD treatments. Although organ-on-a-chip and the work reported in this paper.
organoids are two entirely different strategies, they complement each
other and prove useful in integrated models where both of their ad- Data availability
vantages can be utilized to portray synergism (Reiner et al., 2021).
Furthermore, muti-organ-on-a-chip models are redefining research to No data was used for the research described in the article.
incorporate multiple organ systems that influence disease progression
(Picollet-D’hahan et al., 2021). Such an approach allows the research to Acknowledgment of funding and grant
focus on numerous organs simultaneously to decipher the complex
pathophysiology of PD, taking into account the gut-brain relationship. This work did not receive any grant from funding agencies in the
Improvements in these models will result in incorporating multiomics public, commercial, or not-for-profit sectors.
analysis into the multi-organ-on-a-chip approach, widening the scope of
PD investigation (Picollet-D’hahan et al., 2021). References
Multiomic analysis, sequencing techniques, and gene expression
profiling with computational and various imaging modalities present Aflaki, E., Borger, D.K., Moaven, N., Stubblefield, B.K., Rogers, S.A., Patnaik, S.,
Schoenen, F.J., Westbroek, W., Zheng, W., Sullivan, P., 2016. A new
improved diagnostic methods that can be utilized to enhance disease
glucocerebrosidase chaperone reduces α-synuclein and glycolipid levels in iPSC-
understanding without animal studies. This will eliminate the prospect derived dopaminergic neurons from patients with Gaucher disease and
of interspecies differences that arise in the transfer of research from a parkinsonism. J. Neurosci. 36 (28), 7441–7452. https://doi.org/10.1523/
jneurosci.0636-16.2016.
pre-clinical to a clinical stage (Cassotta et al., 2022). AI digital bio-
Ahn, T.B., Kim, S., Kim, J., Park, S.S., Lee, D., Min, H., Kim, Y., Kim, S., Kim, J.M.,
markers are also being established, opening new areas of exploration. A Kim, H.J., 2008. α-Synuclein gene duplication is present in sporadic Parkinson
study collected data from PD patients by monitoring their nocturnal disease. Neurology 70 (1), 43–49. https://doi.org/10.1212/01.
breathing to predict PD progression. The digital biomarker portrayed wnl.0000271080.53272.c7.
Alam, M., Schmidt, W., 2002. Rotenone destroys dopaminergic neurons and induces
not only disease progression but also allowed disease diagnosis (Yang parkinsonian symptoms in rats. Behav. Brain Res. 136 (1), 317–324. https://doi.org/
et al., 2022). Leveraging frameworks like adverse outcome pathways 10.1016/s0166-4328(02)00180-8.
(AOPs) also aid in categorizing existing knowledge, identifying gaps, Alaylioğlu, M., Dursun, E., Yilmazer, S., Ak, D.G., 2020. A bridge between in vitro and in
vivo studies in neuroscience: organotypic brain slice cultures. Noro. Psikiyatr. Ars.
and guiding future research directions. PD-related AOPs are emerging 57 (4), 333–337.
while scientists are making efforts to integrate the vast PD associated Angelica, F., Alejandro, M., Cristobal, G.-M., Gabriel, N., Milagros, A., Dale, E.E.,
data into pre-existing AOPs (Cassotta et al., 2022). Marcelo, V.-H., Susan, L.h., Patricio, I.-V., Miguel, R.-P., 2013. Similarities between
the binding sites of monoamine oxidase (MAO) from different species — is zebrafish
Transitioning away from animal-based research, integrating human- a useful model for the discovery of novel MAO inhibitors? In: Gandhi Rádis, B. (Ed.),
based cellular models with non-invasive imaging, epidemiological, and An Integrated View of the Molecular Recognition and Toxinology. IntechOpen,
clinical data offers a holistic understanding of PD. Apart from this, Rijeka. https://doi.org/10.5772/35874. Ch. 16.
Arboleda, G., Waters, C., Gibson, R.M., 2005. Metabolic activity. J. Mol. Neurosci. 27,
sharing negative data from animal and cellular models is essential to
65–77. https://doi.org/10.1385/JMN:27:1:065.
predict new directions without experimental duplication (Cassotta et al., Atack, J.R., Shook, B.C., Rassnick, S., Jackson, P.F., Rhodes, K., Drinkenburg, W.H.,
2022). Every model, however, has its own merits and limits and is un- Ahnaou, A., Te Riele, P., Langlois, X., Hrupka, B., 2014. JNJ-40255293, a novel
adenosine A2A/A1 antagonist with efficacy in preclinical models of Parkinson’s
able to completely mimic PD pathology due to the multiple factors and
disease. ACS Chem. Neurosci. 5 (10), 1005–1019. https://doi.org/10.1021/
cells involved in the disease progression. There is, therefore, a need to cn5001606.
identify models based on their features and use a multi-model approach Baiguera, C., Alghisi, M., Pinna, A., Bellucci, A., De Luca, M.A., Frau, L., Morelli, M.,
to look for a more exhaustive approach to unravel PD pathogenesis. Ingrassia, R., Benarese, M., Porrini, V., 2012. Late-onset Parkinsonism in NFκB/c-
Rel-deficient mice. Brain 135 (Pt9), 2750–2765. https://doi.org/10.1093/brain/
aws193.
7. Conclusion Barazzuol, L., Giamogante, F., Brini, M., Calì, T., 2020. PINK1/parkin mediated
mitophagy, Ca2+ signalling, and ER–mitochondria contacts in Parkinson’s disease.
Int. J. Mol. Sci. 21 (5), 1772. https://doi.org/10.3390/ijms21051772.
Various animal models, both neurotoxic and genetic, provide new Barbosa, J.S., Ninkovic, J., 2016. Adult neural stem cell behavior underlying constitutive
insights into the pathogenesis of the disease. However, no animal, in and restorative neurogenesis in zebrafish. Neurogenesis (Austin, Tex.) 3 (1),
vitro and genetic model reproduces the entire spectrum of human PD. e1148101. https://doi.org/10.1080/23262133.2016.1148101.
Basil, A.H., Sim, J.P., Lim, G.G., Lin, S., Chan, H.Y., Engelender, S., Lim, K.L., 2017. AF-6
There is an urgent need for novel experimental models of PD as most of protects against dopaminergic dysfunction and mitochondrial abnormalities in
the neuroprotective drugs developed based on these models failed to Drosophila models of Parkinson’s disease. Front. Cell. Neurosci. 11, 241. https://doi.
pass the clinical trials. Future experimental models of PD involving in org/10.3389/fncel.2017.00241.
Basilicata, P., Pieri, M., Simonelli, A., Capasso, E., Casella, C., Noto, T., Policino, F., Di
vitro cellular models, organoids, organ-on-chip and AI-based models Lorenzo, P., 2022. Diquat poisoning: care management and medico-legal
individually and in combination provide a clear picture of PD as they implications. Toxics 10 (4), 166. https://doi.org/10.3390/toxics10040166.
used cells, tissues and data derived from human patients, and speed up Beal, M., 2010. Parkinson’s disease: a model dilemma. Nature 466, S8–S10. https://doi.
org/10.1038/466S8a, 17310.
the understating of the etiopathogenesis and screening of disease ther-
Belić, M., Bobić, V., Badža, M., Šolaja, N., Đurić-Jovičić, M., Kostić, V.S., neurosurgery,
apeutics. Thus, experimental models play a crucial role in understanding 2019. Artificial intelligence for assisting diagnostics and assessment of Parkinson’s
different pathological mechanisms of human PD and the development of disease—a review. Clin. Neurol. Neurosurg. 105442, 184. https://doi.org/10.1016/
novel potential treatment modalities. j.clineuro.2019.105442.
Benazzouz, A., Breit, S., Koudsie, A., Pollak, P., Krack, P., Benabid, A.L., 2002.
Intraoperative microrecordings of the subthalamic nucleus in Parkinson’s disease.
CRediT authorship contribution statement Mov. Disord. 3, S145–S149. https://doi.org/10.1002/mds.10156.
Berg, D., Postuma, R.B., Adler, C.H., Bloem, B.R., Chan, P., Dubois, B., Gasser, T.,
Goetz, C.G., Halliday, G., Joseph, L., 2015. MDS research criteria for prodromal
Roshan Lal: Conceptualization, Writing – original draft, Writing – Parkinson’s disease. Mov. Disord. 30 (12), 1600–1611. https://doi.org/10.1002/
review & editing. Aditi singh: Writing - manuscript preparation, and mds.26431.
15
Betarbet, R., Sherer, T.B., Greenamyre, J.T., 2002. Animal models of Parkinson’s disease. The future of Parkinson’s disease research: a new paradigm of human-specific
Bioessays 24 (4), 308–318. https://doi.org/10.1002/bies.10067. investigation is necessary… and possible. ALTEX 39 (4), 694–709. https://doi.org/
Betarbet, R., Sherer, T.B., MacKenzie, G., Garcia-Osuna, M., Panov, A.V., Greenamyre, J. 10.14573/altex.2203161.
T., 2000. Chronic systemic pesticide exposure reproduces features of Parkinson’s Cerri, S., Mus, L., Blandini, F., 2019. Parkinson’s disease in women and men: what’s the
disease. Nature neuroscience. Nat. Neurosci. (12), 1301–1306. https://doi.org/ difference? J. Parkinsons Dis. 9 (3), 501–505. https://doi.org/10.3233/jpd-191683.
10.1038/81834. Cha, Y., Park, T.Y., Leblanc, P., Kim, K.S., 2023. Current status and future perspectives on
Bezard, E., Przedborski, S., 2011. A tale on animal models of Parkinson’s disease. Mov. stem cell-based therapies for Parkinson’s disease. J. Move Disord. 16 (1), 22–41.
Disord. 26 (6), 993–1002. https://doi.org/10.1002/mds.23696. Chai, C., Lim, K.L., 2013. Genetic insights into sporadic Parkinson’s disease pathogenesis.
Bieri, G., Gitler, A.D., Brahic, M., 2018. Internalization, axonal transport and release of Curr. Genom. 14 (8), 486–501.
fibrillar forms of alpha-synuclein. Neurobiol. Dis. 109 (Pt B), 219–225. https://doi. Chambers, S.M., Fasano, C.A., Papapetrou, E.P., Tomishima, M., Sadelain, M., Studer, L.,
org/10.1016/j.nbd.2017.03.007. 2009. Highly efficient neural conversion of human ES and iPS cells by dual inhibition
Bisbal, M., Sanchez, M., 2019. Neurotoxicity of the pesticide rotenone on neuronal of SMAD signaling. Nat. Biotechnol. 27 (3), 275–280. https://doi.org/10.1038/
polarization: a mechanistic approach. Neural Regen. Res. 14 (5), 762–766. https:// nbt.1529.
doi.org/10.4103/1673-5374.249847. Chaudhuri, K.R., Prieto-Jurcynska, C., Naidu, Y., Mitra, T., Frades-Payo, B., Tluk, S.,
Bisong, S.A., Brown, R., Osim, E.E., 2010. Comparative effects of Rauwolfia vomitoria Ruessmann, A., Odin, P., Macphee, G., Stocchi, F., 2010. The nondeclaration of
and chlorpromazine on locomotor behaviour and anxiety in mice. nonmotor symptoms of Parkinson’s disease to health care professionals: an
J. Ethnopharmacol. 132 (1), 334–339. https://doi.org/10.1016/j.jep.2010.08.045. international study using the nonmotor symptoms questionnaire. Mov. Disord. 25
Bispo, J.M., Melo, J.E., Gois, A.M., Medeiros, K.A., Silva, R.S., Leal, P.C., Franco, H.S., (6), 704–709. https://doi.org/10.1002/mds.22868.
Souza, M.F., Lins, L.C., Ribeiro, A.M., 2022. Testosterone propionate improves motor Chen, C., Edelstein, L.C., Gélinas, C., 2000. The Rel/NF-κB family directly activates
alterations and dopaminergic damage in the reserpine-induced progressive model of expression of the apoptosis inhibitor Bcl-xL. Mol. Cell Biol. 20 (8), 2687–2695.
Parkinson’s disease. Brain Res. Bull. 187, 162–168. https://doi.org/10.1016/j. https://doi.org/10.1128/mcb.20.8.2687-2695.2000.
brainresbull.2022.06.018. Chesselet, M.-F., Fleming, S., Mortazavi, F., Meurers, B., 2008. Strengths and limitations
Blandini, F., Armentero, M.T., 2012. Animal models of Parkinson’s disease. FEBS J. 279 of genetic mouse models of Parkinson’s disease. Parkinsonism Relat. Disorders 14
(7), 1156–1166. https://doi.org/10.1111/j.1742-4658.2012.08491.x. (Suppl. 2), S84 s7.
Blesa, J., Phani, S., Jackson-Lewis, V., Przedborski, S., 2012. Classic and new animal Chia, K., Klingseisen, A., Sieger, D., Priller, J., 2022. Zebrafish as a model organism for
models of Parkinson’s disease. J. Biomed. Biotechnol. 2012, 845618 https://doi.org/ neurodegenerative disease. Front. Mol. Neurosci. 15, 940484 https://doi.org/
10.1155/2012/845618, 2012. 10.3389/fnmol.2022.940484.
Blesa, J., Przedborski, S., 2014. Parkinson’s disease: animal models and dopaminergic Chlebanowska, P., Tejchman, A., Sułkowski, M., Skrzypek, K., Majka, M., 2020. Use of
cell vulnerability. Front. Neuroanat. 8, 155. https://doi.org/10.3389/ 3D organoids as a model to study idiopathic form of Parkinson’s disease. Disease. Int.
fnana.2014.00155. J. Mol. Sci. 21 (3), 694. https://doi.org/10.3390/ijms21030694.
Bonifati, V., Rizzu, P., Van Baren, M.J., Schaap, O., Breedveld, G.J., Krieger, E., Choudhury, S.P., Bano, S., Sen, S., Suchal, K., Kumar, S., Nikolajeff, F., Dey, S.K.,
Dekker, M.C., Squitieri, F., Ibanez, P., Joosse, M., 2003. Mutations in the DJ-1 gene Sharma, V., 2022. Altered neural cell junctions and ion-channels leading to disrupted
associated with autosomal recessive early-onset parkinsonism. Science 299 (5604), neuron communication in Parkinson’s disease. NPJ. Parkinsons Dis. 8 (1), 66.
256–259. https://doi.org/10.1126/science.1077209. https://doi.org/10.1038/s41531-022-00324-9.
Bonneh-Barkay, D., Reaney, S.H., Langston, W.J., Di Monte, D.A., 2005. Redox cycling of Chung, H.K., Ho, H.-A., Pérez-Acuña, D., Lee, S.J., 2019. Modeling α-synuclein
the herbicide paraquat in microglial cultures. Brain Res. Mol. Brain Res. 134 (1), propagation with preformed fibril injections. J. Mov. Disord. 13 (1), 77–79. https://
52–56. https://doi.org/10.1016/j.molbrainres.2004.11.005. doi.org/10.14802/jmd.19046.e.
Borgs, L., Peyre, E., Alix, P., Hanon, K., Grobarczyk, B., Godin, J.D., Purnelle, A., Cicchetti, F., Drouin-Ouellet, J., Gross, R.E., 2009. Environmental toxins and Parkinson’s
Krusy, N., Maquet, P., Lefebvre, P., 2016. Dopaminergic neurons differentiating from disease: what have we learned from pesticide-induced animal models? Trends
LRRK2 G2019S induced pluripotent stem cells show early neuritic branching defects. Pharmacol. Sci. 30 (9), 475–483. https://doi.org/10.1016/j.tips.2009.06.005.
Sci. Rep. 6, 33377 https://doi.org/10.1038/srep33377. Cicchetti, F., Lapointe, N., Roberge-Tremblay, A., Saint-Pierre, M., Jimenez, L., Ficke, B.
Bové, J., Perier, C., 2012. Neurotoxin-based models of Parkinson’s disease. Neuroscience W., Gross, R.E., 2005. Systemic exposure to paraquat and maneb models early
211, 51–76. https://doi.org/10.1016/j.neuroscience.2011.10.057. Parkinson’s disease in young adult rats. Neurobiol. Dis. 20 (2), 360–371. https://doi.
Bové, J., Prou, D., Perier, C., Przedborski, S., 2005. Toxin-induced models of Parkinson’s org/10.1016/j.nbd.2005.03.018.
disease. NeuroRx 2 (3), 484–494. https://doi.org/10.1602/neurorx.2.3.484. Colapinto, M., Mila, S., Giraudo, S., Stefanazzi, P., Molteni, M., Rossetti, C.,
Braak, H., Del Tredici, K., Rüb, U., De Vos, R.A., Steur, E.N.J., Braak, E., 2003. Staging of Bergamasco, B., Lopiano, L., Fasano, M., 2006. α-Synuclein protects SH-SY5Y cells
brain pathology related to sporadic Parkinson’s disease. Neurobiol. Aging 24 (2), from dopamine toxicity. Biochem. Biophys. Res. Commun. 349 (4), 1294–1300.
197–211. https://doi.org/10.1016/s0197-4580(02)00065-9. https://doi.org/10.1016/j.bbrc.2006.08.163.
Bretaud, S., Allen, C., Ingham, P.W., Bandmann, O., 2007. p53-dependent neuronal cell Cooper, J.F., Van Raamsdonk, J.M., 2018. Modeling Parkinson’s disease in C. elegans.
death in a DJ-1-deficient zebrafish model of Parkinson’s disease. J. Neurochem. 100 J. Parkinsons Dis. 8 (1), 17–32. https://doi.org/10.3233/jpd-171258.
(6), 1626–1635. https://doi.org/10.1111/j.1471-4159.2006.04291.x. Dauer, W., Przedborski, S., 2003. Parkinson’s disease: mechanisms and models. Neuron
Burbulla, L.F., Song, P., Mazzulli, J.R., Zampese, E., Wong, Y.C., Jeon, S., Santos, D.P., 39 (6), 889–909. https://doi.org/10.1016/s0896-6273(03)00568-3.
Blanz, J., Obermaier, C.D., Strojny, C.J.S., 2017. Dopamine oxidation mediates Dave, K.D., De Silva, S., Sheth, N.P., Ramboz, S., Beck, M.J., Quang, C., Switzer III, R.C.,
mitochondrial and lysosomal dysfunction in Parkinson’s disease. Science 357 Ahmad, S.O., Sunkin, S.M., Walker, D., 2014. Phenotypic characterization of
(6357), 1255–1261. https://doi.org/10.1126/science.aam9080. recessive gene knockout rat models of Parkinson’s disease. Neurobiol. Dis. 70,
Byers, B., Cord, B., Nguyen, H.N., Schüle, B., Fenno, L., Lee, P.C., Deisseroth, K., 190–203. https://doi.org/10.1016/j.nbd.2014.06.009.
Langston, J.W., Pera, R.R., Palmer, T.D., 2011. SNCA triplication Parkinson’s Dawson, T.M., 2000. New animal models for Parkinson’s disease. Neuron 39 (6),
patient’s iPSC-derived DA neurons accumulate α-synuclein and are susceptible to 889–909. https://doi.org/10.1016/s0896-6273(03)00568-3.
oxidative stress. PLoS One 6 (11), e26159. https://doi.org/10.1371/journal. Dawson, T.M., Dawson, V.L., 2010. The role of parkin in familial and sporadic
pone.0026159. Parkinson’s disease. Move. Disord. 25 (1), S32–S39. https://doi.org/10.1002/
Cabin, D.E., Gispert-Sanchez, S., Murphy, D., Auburger, G., Myers, R.R., Nussbaum, R.L., mds.22798.
2005. Exacerbated synucleinopathy in mice expressing A53T SNCA on a Snca null Dawson, T.M., Ko, H.S., Dawson, V.L., 2010. Genetic animal models of Parkinson’s
background. Neurobiol. Aging 26 (1), 25–35. https://doi.org/10.1016/j. disease. Neuron 66 (5), 646–661. https://doi.org/10.1016/j.neuron.2010.04.034.
neurobiolaging.2004.02.026, 2005 Jan. De Miranda, B.R., Castro, S.L., Rocha, E.M., Bodle, C.R., Johnson, K.E., Greenamyre, J.T.,
Cagle, B.S., Sturgeon, M.L., O’Brien, J.B., Wilkinson, J.C., Cornell, R.A., Roman, D.L., 2021. The industrial solvent trichloroethylene induces LRRK2 kinase activity and
Doorn, J.A., 2021. Stable expression of the human dopamine transporter in N27 cells dopaminergic. Neurobiol. Dis. 153, 105312.
as an in vitro model for dopamine cell trafficking and metabolism. Toxicol. Vitro 76, De Miranda, B.R., Greenamyre, J.T., 2020. Trichloroethylene, a ubiquitous
105210. https://doi.org/10.1016/j.tiv.2021.105210. environmental contaminant in the risk for Parkinson’s disease. Environ. Sci. Process.
Camacho, L., Sánchez, J., 2015. Biotechnological Use of Fungi for the Degradation of Impacts. 22 (3), 543–554. https://doi.org/10.1039/c9em00578a.
Recalcitrant Agro-Pesticides, 12, pp. 212–214. https://doi.org/10.1016/B978-0-12- Degli Esposti, M., Rugolo, M., Lenaz, G., 1983. Inhibition of the mitochondrial bc1
802794-3.00012-6. complex by dibromothymoquinone. FEBS Lett. 156 (1), 15–19.
Cannon, J.R., Greenamyre, J.T., 2010. Neurotoxic in vivo models of Parkinson’s disease Dekundy, A., Mela, F., Hofmann, M., Danysz, W., 2015. Effects of dopamine uptake
recent advances. Prog. Brain Res. 184, 17–33. https://doi.org/10.1016/s0079-6123 inhibitor MRZ-9547 in animal models of Parkinson’s disease. J. Neural. Transm. 122
(10)84002-6. (6), 809–818. https://doi.org/10.1007/s00702-014-1326-8.
Cannon, J.R., Tapias, V., Na, H.M., Honick, A.S., Drolet, R.E., Greenamyre, J.T., 2009. Deng, H., Wang, P., Jankovic, J., 2018. The genetics of Parkinson disease. Ageing Res.
A highly reproducible rotenone model of Parkinson’s disease. Neurobiol. Dis. 34 (2), Rev. 42, 72–85. https://doi.org/10.1016/j.arr.2017.12.007.
279–290. https://doi.org/10.1016/j.nbd.2009.01.016. Deumens, R., Blokland, A., Prickaerts, J., 2002. Modeling Parkinson’s disease in rats: an
Carlsson, A., Lindqvist, M., Magnusson, T., 1957. 3, 4-Dihydroxyphenylalanine and 5- evaluation of 6-OHDA lesions of the nigrostriatal pathway. Exp. Neurol. 175 (2),
hydroxytryptophan as reserpine antagonists. Nature 180 (4596), 1200. https://doi. 303–317. https://doi.org/10.1006/exnr.2002.7891.
org/10.1038/1801200a0. Devine, M.J., Ryten, M., Vodicka, P., Thomson, A.J., Burdon, T., Houlden, H.,
Carlsson, M., Carlsson, A., 1989. Marked locomotor stimulation in monoamine-depleted Cavaleri, F., Nagano, M., Drummond, N.J., Taanman, J.W., 2011. Parkinson’s
mice following treatment with atropine in combination with clonidine. J. Neural. disease induced pluripotent stem cells with triplication of the α-synuclein locus. Nat.
Transm. Park. Dis. Dement. Sect. 1 (4), 317–322. https://doi.org/10.1007/ Commun. 2, 440. https://doi.org/10.1038/ncomms1453, 440 2.
bf02263486. Di Monte, D., Sandy, M.S., Ekström, G., Smith, M.T., 1986. Comparative studies on the
Cassotta, M., Geerts, H., Harbom, L., Outeiro, T.F., Pediaditakis, I., Reiner, O., mechanisms of paraquat and 1-methyl-4-phenylpyridine (MPP+) cytotoxicity.
Schildknecht, S., Schwamborn, J.C., Bailey, J., Herrmann, K., Hogberg, H.T., 2022.
16
Biochem. Biophys. Res. Commun. 137 (1), 303–309. https://doi.org/10.1016/0006- Fleming, S.M., Tetreault, N.A., Mulligan, C.K., Hutson, C.B., Masliah, E., Chesselet, M.F.,
291x(86)91210-6. 2008. Olfactory deficits in mice overexpressing human wildtype α-synuclein. Eur. J.
Dixit, S., Bohre, K., Singh, Y., Himeur, Y., Mansoor, W., Atalla, S., Srinivasan, K., 2023. Neurosci. 28 (2), 247–256. https://doi.org/10.1111/j.1460-9568.2008.06346.x.
A Comprehensive review on AI-enabled models for Parkinson’s disease diagnosis. Fujimaki, T., Saiki, S., Tashiro, E., Yamada, D., Kitagawa, M., Hattori, N., Imoto, M.J.P.
Electronics 12 (4), 783. https://doi.org/10.3390/electronics12040783, 2023. O., 2014. Identification of licopyranocoumarin and glycyrurol from herbal
Dluzen, D.E., McDermott, J.L., Liu, B., 1996. Estrogen alters MPTP-induced neurotoxicity medicines as neuroprotective compounds for Parkinson’s disease. PLoS One 9 (6),
in female mice: effects on striatal dopamine concentrations and release. e100395. https://doi.org/10.1371/journal.pone.0100395.
J. Neurochem. 66 (2), 658–666. https://doi.org/10.1046/j.1471- Fukui, M., Rodriguiz, R.M., Zhou, J., Jiang, S.X., Phillips, L.E., Caron, M.G., Wetsel, W.,
4159.1996.66020658.x. 2007. Vmat2 heterozygous mutant mice display a depressive-like phenotype.
Dorsey, E.R., Elbaz, A., Nichols, E., Abbasi, N., Abd-Allah, F., Abdelalim, A., Adsuar, J.C., J. Neurosci. 27 (39), 10520–10529. https://doi.org/10.1523/jneurosci.4388-
Ansha, M.G., Brayne, C., Choi, J.Y., 2018. Global, regional, and national burden of 06.2007.
Parkinson’s disease, 1990–2016: a systematic analysis for the Global Burden of Gainetdinov, R.R., Fumagalli, F., Wang, Y.M., Jones, S.R., Levey, A.I., Miller, G.W.,
Disease Study 2016. Lancet Neurol. 18 (5), 459–480. https://doi.org/10.1016/ Caron, M.G., 1998. Increased MPTP neurotoxicity in vesicular monoamine
s1474-4422(18)30499-x. transporter 2 heterozygote knockout mice. J. Neurochem. 70 (5), 1973–1978.
Dorsey, E., Zafar, M., Lettenberger, S.E., Pawlik, M.E., Kinel, D., Frissen, M., https://doi.org/10.1046/j.1471-4159.1998.70051973.x.
Schneider, R.B., Kieburtz, K., Tanner, C.M., De Miranda, B.R., 2023. Galet, B., Cheval, H., Ravassard, P., 2020. Patient-derived midbrain organoids to explore
Trichloroethylene: an invisible cause of Parkinson’s disease? J. Parkinsons Dis. 13 the molecular basis of Parkinson’s disease. Front. Neurol. 11, 1005. https://doi.org/
(2), 203–218. https://doi.org/10.3233/jpd-225047. 10.3389/fneur.2020.01005.
Dovonou, A., Bolduc, C., Soto Linan, V., 2023. Animal models of Parkinson’s disease: Galter, D., Pernold, K., Yoshitake, T., Lindqvist, E., Hoffer, B., Kehr, J., Larsson, N.G.,
bridging the gap between disease hallmarks and research questions. Transl. Olson, L., 2010. MitoPark mice mirror the slow progression of key symptoms and L-
Neurodegener. 12 (1), 36. https://doi.org/10.1186/s40035-023-00368-8. DOPA response in Parkinson’s disease. Gene Brain Behav. 9 (2), 173–178. https://
Duty, S., Jenner, P., 2011. Animal models of Parkinson’s disease: a source of novel doi.org/10.1111/j.1601-183x.2009.00542.x.
treatments and clues to the cause of the disease. Br. J. Pharmacol. 164 (4), Gandhi, P.N., Chen, S.G., Wilson-Delfosse, A.L., 2009. Leucine-rich repeat kinase 2
1357–1391. https://doi.org/10.1111/j.1476-5381.2011.01426.x. (LRRK2): a key player in the pathogenesis of Parkinson’s disease. J. Neurosci. Res.
Efremova, L., Schildknecht, S., Adam, M., Pape, R., Gutbier, S., Hanf, B., Bürkle, A., 87 (6), 1283–1295. https://doi.org/10.1002/jnr.21949.
Leist, M., 2015. Prevention of the degeneration of human dopaminergic neurons in Ganguly, U., Singh, S., Pal, S., Prasad, S., Agrawal, B.K., Saini, R.V., Chakrabarti, S.,
an astrocyte co-culture system allowing endogenous drug metabolism. Br. J. 2021. Alpha-synuclein as a biomarker of Parkinson’s disease: good, but not good
Pharmacol. 172 (16), 4119–4132. https://doi.org/10.1111/bph.13193. enough. Front. Aging Neurosci. 8 (13), 702639.
Ekstrand, M.I., Galter, D., 2009. The MitoPark Mouse–An animal model of Parkinson’s Gao, L., Zhou, W., Symmes, B., Freed, C.R., 2016. Re-cloning the N27 dopamine cell line
disease with impaired respiratory chain function in dopamine neurons. Parkinsonism to improve a cell culture model of Parkinson’s disease. PLoS One 11 (8), e0160847.
Relat. Disorders 15 (Suppl. 3), S185–S188. https://doi.org/10.1016/s1353-8020 https://doi.org/10.1371/journal.pone.0160847.
(09)70811-9. Garcia-Leon, J.A., Vitorica, J., Gutierrez, A., 2019. Use of human pluripotent stem cell-
Ekstrand, M.I., Terzioglu, M., Galter, D., Zhu, S., Hofstetter, C., Lindqvist, E., Thams, S., derived cells for neurodegenerative disease modeling and drug screening platform.
Bergstrand, A., Hansson, F.S., Trifunovic, A., 2007. Progressive parkinsonism in mice Future Med. Chem. 11 (11), 1305–1322.
with respiratory-chain-deficient dopamine neurons. Proc. Natl. Acad. Sci. U. S. A 104 Gelb, D.J., Oliver, E., Gilman, S., 1999. Diagnostic criteria for Parkinson disease. Arch.
(4), 1325–1330. https://doi.org/10.1073/pnas.0605208103. Neurol. 56 (1), 33–39. https://doi.org/10.1001/archneur.56.1.33.
Elfarrash, S., Jensen, P.H., 2021. Organotypic hippocampal slices, an emerging tool to Gitler, A.D., Dhillon, P., Shorter, J., 2017. Neurodegenerative disease: models,
model synucleinopathies. Neural. Regen. Res. 16 (5), 999–1000. mechanisms, and a new hope. Dis. Model Mech. 10 (5), 499–502. https://doi.org/
Elfarrash, S., Jensen, N.M., Ferreira, N., Betzer, C., Thevathasan, J.V., Diekmann, R., 10.1242/dmm.030205, 499-502 10.
Adel, M., Omar, N.M., Boraie, M.Z., Gad, S., Ries, J., Kirik, D., Nabavi, S., Jensen, P. Goedert, M., Masuda-Suzukake, M., Falcon, B.J.B., 2017. Like prions: the propagation of
H., 2019. Organotypic slice culture model demonstrates inter-neuronal spreading of aggregated tau and α-synuclein in neurodegeneration. Brain 140 (2), 266–278.
alpha-synuclein aggregates. Acta Neuropathol. Commun. 7 (1), 213. https://doi. https://doi.org/10.1093/brain/aww230.
org/10.1186/s40478-019-0865-5. Godoy, R., Hua, K., Kalyn, M., Cusson, V.M., Anisman, H., Ekker, M., 2020.
Erro, R., Schneider, S.A., Stamelou, M., Quinn, N.P., Bhatia, K.P., Dopaminergic neurons regenerate following chemogenetic ablation in the olfactory
Neurosurgery, Psychiatry, 2016. What do patients with scans without evidence of bulb of adult Zebrafish (Danio rerio). Sci. Rep. 10 (1), 12825 https://doi.org/
dopaminergic deficit (SWEDD) have? New evidence and continuing controversies. 10.1038/s41598-020-69734-0.
J. Neurol. Neurosurg. Psychiatry 87 (3), 319–323. https://doi.org/10.1136/jnnp- Goldberg, M.S., Fleming, S.M., Palacino, J.J., Cepeda, C., Lam, H.A., Bhatnagar, A.,
2014-310256. Meloni, E.G., Wu, N., Ackerson, L.C., Klapstein, G.J., 2003. Parkin-deficient mice
Eum, W.S., Shin, M.J., Lee, C.H., Yeo, H.J., Yeo, E.J., Choi, Y.J., Kwon, H.J., Kim, D.S., exhibit nigrostriatal deficits but not loss of dopaminergic neurons. J. Biol. Chem. 278
Kwon, O.S., Lee, K.W., 2019. Neuroprotective effects of Tat-ATOX1 protein against (44), 43628–43635. https://doi.org/10.1074/jbc.m308947200.
MPP+-induced SH-SY5Y cell deaths and in MPTP-induced mouse model of Goldberg, M.S., Pisani, A., Haburcak, M., Vortherms, T.A., Kitada, T., Costa, C., Tong, Y.,
Parkinson’s disease. Biochimie 156, 158–168. https://doi.org/10.1016/j. Martella, G., Tscherter, A., Martins, A., 2005. Nigrostriatal dopaminergic deficits and
biochi.2018.10.010. hypokinesia caused by inactivation of the familial Parkinsonism-linked gene DJ-1.
Falkenburger, B.H., Schulz, J.B., 2006. Limitations of cellular models in Parkinson’s Neuron 45 (4), 489–496. https://doi.org/10.1016/j.neuron.2005.01.041.
disease research. J. Neural. Transm. Suppl. (70), 261–268. https://doi.org/10.1007/ Goldstein, J.M., Barnett, A., Malick, J.B., 1975. The evaluation of anti-Parkinson drugs
978-3-211-45295-0_40. on reserpine-induced rigidity in rats. Eur. J. Pharmacol. 33 (1), 183–188. https://
Feany, M.B., Bender, W.W., 2000. A Drosophila model of Parkinson’s disease. Nature 404 doi.org/10.1016/0014-2999(75)90154-5.
(6776), 394–398. https://doi.org/10.1038/35006074, 2000. Gómez-Benito, M., Granado, N., García-Sanz, P., 2020. Michel A, dumoulin M, moratalla
Fernagut, P.O., Chesselet, M.F., 2004. Alpha-synuclein and transgenic mouse models. R. Modeling Parkinson’s disease with the alpha-synuclein protein. Front. Pharmacol.
Neurobiol. Dis. 17 (2), 123–130. https://doi.org/10.1016/j.nbd.2004.07.001. 11, 356. https://doi.org/10.3389/fphar.2020.00356, 2020.
Fernandes, H.J., Hartfield, E.M., Christian, H.C., Emmanoulidou, E., Zheng, Y., Booth, H., Gong, P., Deng, F., Zhang, W., Ji, J., Liu, J., Sun, Y., Hu, J., 2017. Tectorigenin attenuates
Bogetofte, H., Lang, C., Ryan, B.J., Sardi, S.P., 2016. ER stress and autophagic the MPP+-induced SH-SY5Y cell damage, indicating a potential beneficial role in
perturbations lead to elevated extracellular α-synuclein in GBA-N370S Parkinson’s Parkinson’s disease by oxidative stress inhibition. Exp. Ther. Med. 14 (5),
iPSC-derived dopamine neurons. Stem Cell Rep. 6 (3), 342–356. https://doi.org/ 4431–4437. https://doi.org/10.3892/etm.2017.5049.
10.1016/j.stemcr.2016.01.013. Gopinath, A., Mackie, P., Hashimi, B., Buchanan, A.M., Smith, A.R., Bouchard, R.,
Fernandes, V.S., Ribeiro, A.M., Melo, T.G., Godinho, M., Barbosa, F.F., Medeiros, D.S., Shaw, G., Badov, M., Saadatpour, L., Gittis, A., Ramirez-Zamora, A., Okun, M.S.,
Munguba, H., Silva, R.H., 2008. Memory impairment induced by low doses of Streit, W.J., Hashemi, P., Khoshbouei, H., 2022. DAT and TH expression marks
reserpine in rats: possible relationship with emotional processing deficits in human Parkinson’s disease in peripheral immune cells. NPJ Parkinson’s Dis. 8 (1),
Parkinson disease. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 32 (6), 72. https://doi.org/10.1038/s41531-022-00333-8.
1479–1483. https://doi.org/10.1016/j.pnpbp.2008.05.004. Gubellini, P., Kachidian, P., 2015. Animal models of Parkinson’s disease: an updated
Fernández-Santiago, R., Merkel, A., Castellano, G., Heath, S., Raya, Á., Tolosa, E., overview. Revue neurologique. Rev. Neurol. (Paris) 71 (11), 750–761. https://doi.
Martí, M.-J., Consiglio, A., Ezquerra, M., 2019. Whole-genome DNA hyper- org/10.1016/j.neurol.2015.07.011.
methylation in iPSC-derived dopaminergic neurons from Parkinson’s disease Hamet, P., Tremblay, J.J.M., 2017. Artificial intelligence in medicine. Artif. Intell. Med.
patients. Clin. Epigenetics 11 (1), 108–114. https://doi.org/10.1186/s13148-019- 1, 1–2. https://doi.org/10.1016/j.artmed.2017.06.011.
0701-6. Hammond, C., Bergman, H., Brown, P., 2007. Pathological synchronization in
Fernández, B., Ferrer, I., Gil, F., Hilfiker, S., 2017. Biomonitorization of iron Parkinson’s disease: networks, models and treatments. Trends Neurosci. 30 (7),
accumulation in the substantia nigra from Lewy body disease patients. Toxicol. Rep. 357–364. https://doi.org/10.1016/j.tins.2007.05.004.
4, 188–193. https://doi.org/10.1016/j.toxrep.2017.03.005. Hawke, S.H.B., Davies, L., Pamphlett, R., Guo, Y., Pollard, J., McLeod, J., 1991.
Fett, M.E., Pilsl, A., Paquet, D., Van Bebber, F., Haass, C., Tatzelt, J., Schmid, B., Vasculitic neuropathy: a clinical and pathological study. Brain 114 (Pt 5),
Winklhofer, K.F., 2010. Parkin is protective against proteotoxic stress in a transgenic 2175–2190. https://doi.org/10.1093/brain/114.5.2175.
zebrafish model. PLoS One 5 (7), e11783. https://doi.org/10.1371/journal. Hedrich, K., Djarmati, A., Schäfer, N., Hering, R., Wellenbrock, C., Weiss, P.H., Hilker, R.,
pone.0011783. Vieregge, P., Ozelius, L.J., Heutink, P., Bonifati, V., Schwinger, E., Lang, A.E.,
Fleming, S.M., Salcedo, J., Fernagut, P.O., Rockenstein, E., Masliah, E., Levine, M.S., Noth, J., Bressman, S.B., Pramstaller, P.P., Riess, O., Klein, C., 2004. DJ-1 (PARK7)
Chesselet, M.F., 2004. Early and progressive sensorimotor anomalies in mice mutations are less frequent than Parkin (PARK2) mutations in early-onset Parkinson
overexpressing wild-type human α-synuclein. J. Neurosci. 24 (42), 9434–9440. disease. Neurology 62 (3), 389–394. https://doi.org/10.1212/01.
https://doi.org/10.1523/jneurosci.3080-04.2004. wnl.0000113022.51739.88.
17
Heeringa, M.J., Abercrombie, E.D., 1995. Biochemistry of somatodendritic dopamine glucocerebrosidase and α-synuclein mutations. Ann. Neurol. 90 (3), 490–505.
release in substantia nigra: an in vivo comparison with striatal dopamine release. https://doi.org/10.1002/ana.26166.
J. Neurochem. 65 (1), 192–200. https://doi.org/10.1046/j.1471- Johnson, M.E., Bobrovskaya, L., 2015. An update on the rotenone models of Parkinson’s
4159.1995.65010192.x. disease: their ability to reproduce the features of clinical disease and model
Heman-Ackah, S.M., Manzano, R., Hoozemans, J.J., Scheper, W., Flynn, R., Haerty, W., gene–environment interactions. Neurotoxicology 46, 101–116. https://doi.org/
Cowley, S.A., Bassett, A.R., Wood, M.J., Alpha-synuclein induces the unfolded 10.1016/j.neuro.2014.12.002.
protein response in Parkinson’s disease SNCA triplication iPSC-derived neurons. Kadkhodaei, B., Ito, T., Joodmardi, E., Mattsson, B., Rouillard, C., Carta, M.,
Hum. Mol. Genet. 26(22),4441-4450. https://doi.org/10.1093/hmg/ddx331. Muramatsu, S.-I., Sumi-Ichinose, C., Nomura, T., Metzger, D., 2009. Nurr1 is
Hinkle, K.M., Yue, M., Behrouz, B., Dächsel, J.C., Lincoln, S.J., Bowles, E.E., Beevers, J. required for maintenance of maturing and adult midbrain dopamine neurons.
E., Dugger, B., Winner, B., Prots, I., 2012. LRRK2 knockout mice have an intact J. Neurosci. 29 (50), 15923–15932. https://doi.org/10.1523/jneurosci.3910-
dopaminergic system but display alterations in exploratory and motor co-ordination 09.2009.
behaviors. Mol. Neurodegener. 7, 25. https://doi.org/10.1186/1750-1326-7-25. Kalinderi, K., Bostantjopoulou, S., Fidani, L., 2016. The genetic background of
Hirth, F., 2010. Drosophila melanogaster in the study of human neurodegeneration. CNS Parkinson’s disease: current progress and future prospects. Acta Neurol. Scand. 134
Neurol. Disord.: Drug Targets 9 (4), 504–523. https://doi.org/10.2174/ (5), 314–326. https://doi.org/10.1111/ane.12563.
187152710791556104. Karpenko, M.N., Muruzheva, Z.M., Ilyechova, E.Y., Babich, P.S., Puchkova, L.V., 2023.
Hisahara, S., Shimohama, S., 2011. Dopamine receptors and Parkinson’s disease. Int. J. Abnormalities in copper status associated with an elevated risk of Parkinson’s
Med. Chem. 2011, 403039. phenotype development. Antioxidants 12 (9), 1654. https://doi.org/10.3390/
Howell, M.J., Schenck, C.H., 2015. Rapid eye movement sleep behavior disorder and antiox12091654.
neurodegenerative disease. JAMA Neurol. 72 (6), 707–712. https://doi.org/ Karpinar, D.P., Balija, M.B.G., Kügler, S., Opazo, F., Rezaei-Ghaleh, N., Wender, N.,
10.1001/jamaneurol.2014.4563. Kim, H.Y., Taschenberger, G., Falkenburger, B.H., Heise, H., 2009. Pre-fibrillar
Hsieh, C.-H., Shaltouki, A., Gonzalez, A.E., da Cruz, A.B., Burbulla, L.F., Lawrence, E.S., α-synuclein variants with impaired β-structure increase neurotoxicity in Parkinson’s
Schüle, B., Krainc, D., Palmer, T.D., Wang, X., 2016. Functional impairment in miro disease models. EMBO J. 28 (20), 3256–3268. https://doi.org/10.1038/
degradation and mitophagy is a shared feature in familial and sporadic Parkinson’s emboj.2009.257.
disease. Cell Stem Cell 19 (6), 709–724. https://doi.org/10.1016/j. Kasabova-Angelova, A., Tzankova, D., Mitkov, J., Georgieva, M., Tzankova, V.,
stem.2016.08.002. Zlatkov, A., Kondeva-Burdina, M., 2020. Xanthine derivatives as agents affecting
Hutchison, W., Allan, R., Opitz, H., Levy, R., Dostrovsky, J., Lang, A., Lozano, A.M., non-dopaminergic neuroprotection in Parkinson’s disease. Curr. Med. Chem. 27
1998. Neurophysiological identification of the subthalamic nucleus in surgery for (12), 2021–2036. https://doi.org/10.2174/0929867325666180821153316.
Parkinson’s disease. Ann. Neurol. 44 (4), 622–628. https://doi.org/10.1002/ Ke, M., Chong, C.M., Zhu, Q., Zhang, K., Cai, C.Z., Lu, J.H., Qin, D., Su, H., 2021.
ana.410440407, 622-628 44. Comprehensive perspectives on experimental models for Parkinson’s disease. Aging
Hwang, D.Y., Fleming, S.M., Ardayfio, P., Moran-Gates, T., Kim, H., Tarazi, F.I., Dis 12, 223–246. https://doi.org/10.14336/ad.2020.0331.
Chesselet, M.-F., Kim, K.S., 2005. 3, 4-dihydroxyphenylalanine reverses the motor Kelava, I., Lancaster, M.A., 2016. Dishing out mini-brains: current progress and future
deficits in Pitx3-deficient aphakia mice: behavioral characterization of a novel prospects in brain organoid research. Dev. Biol. 420 (2), 199–209. https://doi.org/
genetic model of Parkinson’s disease. J. Neurosci. 25 (8), 2132–2137. https://doi. 10.1016/j.ydbio.2016.06.037.
org/10.1523/jneurosci.3718-04.2005. Kim, M.-H., Kim, D., Sung, J.H., 2021. A Gut-Brain Axis-on-a-Chip for studying transport
Hwang, D.Y., Hong, S., Jeong, J.W., Choi, S., Kim, H., Kim, J., Kim, K.S., 2009. Vesicular across epithelial and endothelial barriers. J. Ind. Eng. Chem. 101 (25), 126–134.
monoamine transporter 2 and dopamine transporter are molecular targets of Pitx3 in https://doi.org/10.1016/j.jiec.2021.06.021.
the ventral midbrain dopamine neurons. J. Neurochem. 111 (5), 1202–1212. Kim, R.H., Smith, P.D., Aleyasin, H., Hayley, S., Mount, M.P., Pownall, S., Wakeham, A.,
https://doi.org/10.1111/j.1471-4159.2009.06404.x. You-Ten, A.J., Kalia, S.K., Horne, P., 2005. Hypersensitivity of DJ-1-deficient mice to
Ikeda, M., Kawarabayashi, T., Harigaya, Y., Sasaki, A., Yamada, S., Matsubara, E., 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyrindine (MPTP) and oxidative stress. Proc.
Murakami, T., Tanaka, Y., Kurata, T., Wuhua, X., 2009. Motor impairment and Natl. Acad. Sci. U. S. A 102 (14), 5215–5220. https://doi.org/10.1073/
aberrant production of neurochemicals in human α-synuclein A30P+ A53T pnas.0501282102.
transgenic mice with α-synuclein pathology. Brain Res. 1250, 232–241. https://doi. Kim, S., Yun, S.P., Lee, S., Umanah, G.E., Bandaru, V.V.R., Yin, X., Rhee, P.,
org/10.1016/j.brainres.2008.10.011. Karuppagounder, S.S., Kwon, S.H., Lee, H., 2018. GBA1 deficiency negatively affects
Imai, Y., Gehrke, S., Wang, H.Q., Takahashi, R., Hasegawa, K., Oota, E., Lu, B., 2008. physiological α-synuclein tetramers and related multimers. Proc. Natl. Acad. Sci. U.
Phosphorylation of 4E-BP by LRRK2 affects the maintenance of dopaminergic S. A 115 (4), 798–803. https://doi.org/10.1073/pnas.1700465115.
neurons in Drosophila. EMBO J. 27 (18), 2432–2443. https://doi.org/10.1038/ Kin, K., Yasuhara, T., Kameda, M., 2019. Animal models for Parkinson’s disease research:
emboj.2008.163. trends in the 2000s. Int. J. Mol. Sci. 20 (21), 5402. https://doi.org/10.3390/
Inden, M., Kitamura, Y., Abe, M., Tamaki, A., Takata, K., Taniguchi, T.J.B., Bulletin, P., ijms20215402.
2011. Parkinsonian rotenone mouse model: reevaluation of long-term Kitada, T., Pisani, A., Porter, D.R., Yamaguchi, H., Tscherter, A., Martella, G., Bonsi, P.,
administration of rotenone in C57BL/6 mice. Biol. Pharm. Bull. 34 (1), 92–96. Zhang, C., Pothos, E.N., Shen, J., 2007. Impaired dopamine release and synaptic
https://doi.org/10.1248/bpb.34.92. plasticity in the striatum of PINK1-deficient mice. Proc. Natl. Acad. Sci. U. S. A 104
Islam, M.S., Azim, F., Saju, H., Zargaran, A., Shirzad, M., Kamal, M., Fatema, K., (27), 11441–11446. https://doi.org/10.1073/pnas.0702717104.
Rehman, S., Azad, M.M., Ebrahimi-Barough, S., 2021. Pesticides and Parkinson’s Koob, A.O., Ubhi, K., Paulsson, J.F., Kelly, J., Rockenstein, E., Mante, M., Adame, A.,
disease: current and future perspective. J. Chem. Neuroanat. 115, 101966 https:// Masliah, E., 2010. Lovastatin ameliorates α-synuclein accumulation and oxidation in
doi.org/10.1016/j.jchemneu.2021.101966. transgenic mouse models of α-synucleinopathies. Exp. Neurol. 221 (2), 267–274.
Jackson-Lewis, V., Blesa, J., Przedborski, S., 2012. Animal models of Parkinson’s disease. https://doi.org/10.1016/j.expneurol.2009.11.015.
Parkinsonism Relat. Disorders 1, S183–S185. https://doi.org/10.1016/s1353-8020 Kulkarni, S.K., Bishnoi, M., Chopra, K., 2009. In vivo microdialysis studies of striatal level
(11)70057-8. of neurotransmitters after haloperidol and chlorpromazine administration. Indian J.
Jackson-Lewis, V., Przedborski, S., 2007. Protocol for the MPTP mouse model of Exp. Biol. 47 (2), 91–97. PMID:19374163.
Parkinson’s disease. Nat. Protoc. 2 (1), 141–151. https://doi.org/10.1038/ Kumar, A., Cookson, M.R., 2011. The role of LRRK2 dysfunction in Parkinson’s disease.
nprot.2006.342. Expet Rev. Mol. Med. 13, e20.
Jankovic, J., Chen, S., Le, W., 2005. The role of Nurr1 in the development of Kumar, A., Leinisch, F., Kadiiska, M.B., Corbett, J., Mason, R.P., 2016. Formation and
dopaminergic neurons and Parkinson’s disease. Prog. Neurobiol. 77 (1–2), 128–138. implications of alpha-synuclein radical in maneb-and paraquat-induced models of
https://doi.org/10.1016/j.pneurobio.2005.09.001. Parkinson’s disease. Mol. Neurobiol. 53 (5), 2983–2994. https://doi.org/10.1007/
Javitch, J.A., D’Amato, R.J., Strittmatter, S.M., Snyder, S.H., 1985. Parkinsonism- s12035-015-9179-1.
inducing neurotoxin, N-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine: uptake of the Kwakye, G.F., Paoliello, M.M., Mukhopadhyay, S., Bowman, A.B., Aschner, M., 2015.
metabolite N-methyl-4-phenylpyridine by dopamine neurons explains selective Manganese-induced parkinsonism and Parkinson’s disease: shared and
toxicity. Proc. Natl. Acad. Sci. U. S. A 82 (7), 2173–2177. https://doi.org/10.1073/ distinguishable features. Int. J. Environ. Res. Publ. Health 12, 7519–7540. https://
pnas.82.7.2173. doi.org/10.3390/ijerph120707519.
Jiang, F., Jiang, Y., Zhi, H., Dong, Y., Li, H., Ma, S., Wang, Y., Dong, Q., Shen, H., Kwon, D.Y., Kwon, Y., Kim, J.W., 2018. Quantitative analysis of finger and forearm
Wang, Y., 2017. Artificial intelligence in healthcare: past, present and future. Stroke movements in patients with off state early stage Parkinson’s disease and scans
Vasc. Neurol. 2 (4), 230–243. without evidence of dopaminergic deficit (SWEDD). Parkinsonism Relat. Disorders
Jiang, H., Ren, Y., Yuen, E.Y., Zhong, P., Ghaedi, M., Hu, Z., Azabdaftari, G., Nakaso, K., 57, 33–38. https://doi.org/10.1016/j.parkreldis.2018.07.012.
Yan, Z., Feng, J., 2012. Parkin controls dopamine utilization in human midbrain Langston, J.W., Ballard, P., Tetrud, J.W., Irwin, I., 1983. Chronic Parkinsonism in
dopaminergic neurons derived from induced pluripotent stem cells. Nat. Commun. 3, humans due to a product of meperidine-analog synthesis. Science 219 (4587),
668. https://doi.org/10.1038/ncomms1669. 979–980. https://doi.org/10.1126/science.6823561.
Jiang, S., Berger, S., Hu, Y., Bartsch, D., Tian, Y., 2020. Alterations of the motor and Lázaro, D.F., Pavlou, M.A.S., Outeiro, T.F., 2017. Cellular models as tools for the study of
olfactory functions related to Parkinson’s disease in transgenic mice with a VMAT2- the role of alpha-synuclein in Parkinson’s disease. Exp. Neurol. 298 (Pt B), 162–171.
deficiency in dopaminergic neurons. Front. Neurosci. 14, 356. https://doi.org/ https://doi.org/10.1016/j.expneurol.2017.05.007.
10.3389/fnins.2020.00356. Lazarou, M., Narendra, D.P., Jin, S.M., Tekle, E., Banerjee, S., Youle, R.J., 2013. PINK1
Jo, J., Xiao, Y., Sun, A.X., Cukuroglu, E., Tran, H.-D., Göke, J., Tan, Z.Y., Saw, T.Y., drives Parkin self-association and HECT-like E3 activity upstream of mitochondrial
Tan, C.-P., Lokman, H.J., 2016. Midbrain-like organoids from human pluripotent binding. J. Cell Biol. 200 (2), 163–172. https://doi.org/10.1083/jcb.201210111.
stem cells contain functional dopaminergic and neuromelanin-producing neurons. Le, W., Sayana, P., Jankovic, J., 2014. Animal models of Parkinson’s disease: a gateway
Cell Stem Cell 9 (2), 248–257. https://doi.org/10.1016/j.stem.2016.07.005. to therapeutics? 11 (1), 92–110. https://doi.org/10.1007/s13311-013-0234-1.
Jo, J., Yang, L., Tran, H.D., Yu, W., Sun, A.X., Chang, Y.Y., Jung, B.C., Lee, S.J., Saw, T.Y., Leão, A.H., Sarmento-Silva, A.J., Santos, J.R., Ribeiro, A.M., Silva, R.H., 2015.
Xiao, B., 2021. Lewy body–like inclusions in human midbrain organoids carrying Molecular, neurochemical, and behavioral hallmarks of reserpine as a model for
18
Parkinson’s disease: new perspectives to a long-standing model. Brain Pathol. 25 (4), reduces pathological α-synuclein and restores lysosomal function in Parkinson’s
377–390. https://doi.org/10.1111/bpa.12253. patient midbrain neurons. J. Neurosci. 36 (29), 7693–7706. https://doi.org/
Lee, V.M.Y., Trojanowski, J.Q., 2006. Mechanisms of Parkinson’s disease linked to 10.1523/jneurosci.0628-16.2016.
pathological α-synuclein: new targets for drug discovery. Neuron 52 (1), 33–38. McAllum, E.J., Finkelstein, D.I., 2016. Metals in Alzheimer’s and Parkinson’s disease:
https://doi.org/10.1016/j.neuron.2006.09.026. relevance to dementia with lewy bodies. J. Mol. Neurosci. 60 (3), 279–288. https://
Leung, C.M., De Haan, P., Ronaldson-Bouchard, K., Kim, G.A., Ko, J., Rho, H.S., Chen, Z., doi.org/10.1007/s12031-016-0809-5.
Habibovic, P., Jeon, N.L., Takayama, S., 2022. A guide to the organ-on-a-chip. Nat. McGregor, M.M., Nelson, A.B., 2019. Circuit mechanisms of Parkinson’s disease. Neuron
Rev. Methods Primers 2, 33. https://doi.org/10.1038/s43586-022-00118-63, 2022. 101 (6), 1042–1056. https://doi.org/10.1016/j.neuron.2019.03.004.
Li, J., Dani, J.A., Le, W., 2009a. The role of transcription factor Pitx3 in dopamine neuron Meissner, W., Hill, M.P., Tison, F., Gross, C.E., Bezard, E., 2004. Neuroprotective
development and Parkinson’s disease. Current topics in medicinal chemistry. Curr. strategies for Parkinson’s disease: conceptual limits of animal models and clinical
Top Med. Chem. 9 (10), 855–859. http://www.ncbi.nlm.nih.gov/pmc/articles/pmc trials. Trends Pharmacol. Sci. 25 (5), 249–253. https://doi.org/10.1016/j.
2872921/. tips.2004.03.003.
Li, S., Ritz, B., Gong, Y., Cockburn, M., Folle, A.D., Del Rosario, I., Yu, Y., Zhang, K., Meredith, G.E., Kang, U.J., 2006. Behavioral models of Parkinson’s disease in rodents: a
Castro, E., Keener, A.M., Bronstein, J., Paul, K.C., 2023. Proximity to residential and new look at an old problem. Mov. Disord. 21 (10), 1595–1606. https://doi.org/
workplace pesticides application and the risk of progression of Parkinson’s diseases 10.1002/mds.21010.
in Central California. Sci. Total Environ. 864, 160851 https://doi.org/10.1016/j. Meredith, G.E., Rademacher, D.J., 2011. MPTP mouse models of Parkinson’s disease: an
scitotenv.2022.160851. update. J. Parkinsons Dis. 1 (1), 19–33. https://doi.org/10.3233/jpd-2011-11023.
Li, Y., Hou, L.X., Aktiv, A., Dahlström, A., 2007. Studies of the central nervous system- Miyazaki, I., Asanuma, M., 2020. The rotenone models reproducing central and
derived CAD cell line, a suitable model for intraneuronal transport studies? peripheral features of Parkinson’s disease. NeuroSci 1 (1), 1–14. https://doi.org/
J. Neurosci. Res. 85 (12), 2601–2609. https://doi.org/10.1002/jnr.21216. 10.3390/neurosci1010001.
Li, Y., Liu, W., Oo, T.F., Wang, L., Tang, Y., Jackson-Lewis, V., Zhou, C., Geghman, K., Milosevic, L., Gramer, R., Kim, T.H., Algarni, M., Fasano, A., Kalia, S.K., Hodaie, M.,
Bogdanov, M., Przedborski, S., 2009b. Mutant LRRK2 R1441G BAC transgenic mice Lozano, A.M., Popovic, M.R., Hutchison, W.D., 2019. Modulation of inhibitory
recapitulate cardinal features of Parkinson’s disease. Nat. Neurosci. 12 (7), 826–828. plasticity in basal ganglia output nuclei of patients with Parkinson’s disease.
https://doi.org/10.1038/nn.2349. Neurobiol. Dis. 124, 46–56. https://doi.org/10.1016/j.nbd.2018.10.020.
Li, Y., Yin, Q., Wang, B., Shen, T., Luo, W., Liu, T., 2022. Preclinical reserpine models Miyagi, M., Arai, N., Taya, F., Itoh, F., Komatsu, Y., Kojima, M., Isaji, M., 1996. Effect of
recapitulating motor and non-motor features of Parkinson’s disease: roles of cabergoline, a long-acting dopamine D2 agonist, on reserpine-treated rodents. Biol.
epigenetic upregulation of alpha-synuclein and autophagy impairment. Front. Pharm. Bull. 19 (11), 1499–1502. https://doi.org/10.1248/bpb.19.1499.
Pharmacol. 12 (13), 944376 https://doi.org/10.3389/fphar.2022.944376. Montes, S., Rivera-Mancia, S., Diaz-Ruiz, A., Tristan-Lopez, L., Rios, C., 2014. Copper and
Lim, Y., Kehm, V.M., Li, C., Trojanowski, J.Q., Lee, V.M.Y., 2010. Forebrain copper proteins in Parkinson’s disease. Oxid. Med. Cell. Longev. 2014, 147251
overexpression of α-synuclein leads to early postnatal hippocampal neuron loss and https://doi.org/10.1155/2014/147251.
synaptic disruption. Exp. Neurol. 221 (1), 86–97. https://doi.org/10.1016/j. Monzel, A.S., Smits, L.M., Hemmer, K., Hachi, S., Moreno, E.L., van Wuellen, T.,
expneurol.2009.10.005. Jarazo, J., Walter, J., Brüggemann, I., Boussaad, I., 2017. Derivation of human
Lin, Q.S., Chen, P., Wang, W.X., Lin, C.C., Zhou, Y., Yu, L.H., Lin, Y.X., Xu, Y.F., Kang, D. midbrain-specific organoids from neuroepithelial stem cells. Stem Cell Rep. 8 (5),
Z., 2020. RIP1/RIP3/MLKL mediates dopaminergic neuron necroptosis in a mouse 1144–1154. https://doi.org/10.1016/j.stemcr.2017.03.010.
model of Parkinson disease. Lab. Invest. 100 (3), 503–511. https://doi.org/10.1038/ Moudio, S., Rodin, F., Albargothy, N.J., Karlsson, U., Reyes, J.F., Hallbeck, M., 2022.
s41374-019-0319-5. Exposure of α-synuclein aggregates to organotypic slice cultures recapitulates key
Lin, X., Parisiadou, L., Gu, X.L., Wang, L., Shim, H., Sun, L., Xie, C., Long, C.X., Yang, W. molecular features of Parkinson’s disease. Front. Neurol. 13, 826102.
J., Ding, J., 2009. Leucine-rich repeat kinase 2 regulates the progression of Muthukumaran, K., Leahy, S., Harrison, K., Sikorska, M., Sandhu, J.K., Cohen, J.,
neuropathology induced by Parkinson’s-disease-related mutant α-synuclein. Neuron Keshan, C., Lopatin, D., Miller, H., Borowy-Borowski, H., 2014. Orally delivered
64 (6), 807–827. https://doi.org/10.1016/j.neuron.2009.11.006. water soluble Coenzyme Q 10 (Ubisol-Q 10) blocks on-going neurodegeneration in
Lindholm, D., Mäkelä, J., Di Liberto, V., Mudò, G., Belluardo, N., Eriksson, O., rats exposed to paraquat: potential for therapeutic application in Parkinson’s
Saarma, M., 2016. Current disease modifying approaches to treat Parkinson’s disease. BMC Neurosci. 15, 21. https://doi.org/10.1186/1471-2202-15-21.
disease. Cell Mol. Life Sci. 73 (7), 1365–1379. https://doi.org/10.1007/s00018-0 Nadig, A.P.R., Huwaimel, B., Alobaida, A., Khafagy, E.S., Alotaibi, H.F., Moin, A., Lila, A.
15-2101-1. S.A., Suman, M.S., Krishna, K.L., 2022. Manganese chloride (MnCl(2)) induced novel
López de Maturana, R., Lang, V., Zubiarrain, A., Sousa, A., Vázquez, N., Gorostidi, A., model of Parkinson’s disease in adult Zebrafish; Involvement of oxidative stress,
Águila, J., López de Munain, A., Rodríguez, M., Sánchez-Pernaute, R.J., 2016. neuroinflammation and apoptosis pathway. Biomed. Pharmacother. 155, 113697
Mutations in LRRK2 impair NF-κB pathway in iPSC-derived neurons. https://doi.org/10.1016/j.biopha.2022.113697.
J. Neuroinflammation 13 (1), 295. https://doi.org/10.1186/s12974-016-0761-x. Nagamura, Y., Terawaki, K., Uezono, Y., Tsukada, T., 2014. Enhancement of
Lu, Y., Zhang, X., Zhao, L., Yang, C., Pan, L., Li, C., Liu, K., Bai, G., Gao, H., Yan, Z.J.F.i. catecholamine release from PC12 cells by the traditional Japanese medicine,
N., 2018. Metabolic disturbances in the striatum and substantia nigra in the onset rikkunshito. BMC Compl. Alternative Med. 14, 256. https://doi.org/10.1186/1472-
and progression of MPTP-induced Parkinsonism model. Front. Neurosci. 12, 90. 6882-14-256.
https://doi.org/10.3389/fnins.2018.00090. Nagoshi, E., 2018. Drosophila models of sporadic Parkinson’s disease. Int. J. Mol. Sci. 26
Luthra, P.M., Barodia, S.K., Raghubir, R., 2009. Antagonism of haloperidol-induced swim (11), 3343. https://doi.org/10.3390/ijms19113343, 19.
impairment in L-dopa and caffeine treated mice: a pre-clinical model to study Narayan, S., Liew, Z., Bronstein, J.M., Ritz, B., 2017. Occupational pesticide use and
Parkinson’s disease. J. Neurosci. Methods 178 (2), 284–290. https://doi.org/ Parkinson’s disease in the Parkinson Environment Gene (PEG) study. Environ. Int.
10.1016/j.jneumeth.2008.12.019. 107, 266–273. https://doi.org/10.1016/j.envint.2017.04.010.
Maclagan, L.C., Visanji, N.P., Cheng, Y., Tadrous, M., Lacoste, A.M., Kalia, L.V., Narendra, D.P., Jin, S.M., Tanaka, A., Suen, D.F., Gautier, C.A., Shen, J., Cookson, M.R.,
Bronskill, S.E., Marras, C.J.P., Safety, D., 2020. Identifying drugs with disease- Youle, R.J., 2010. PINK1 is selectively stabilized on impaired mitochondria to
modifying potential in Parkinson’s disease using artificial intelligence and activate Parkin. PLoS Biol. 8 (1), e1000298 https://doi.org/10.1371/journal.
pharmacoepidemiology. Pharmacoepidemiol. Drug Saf. 29 (8), 864–872. https:// pbio.1000298.
doi.org/10.1002/pds.5015. Nashimoto, Y., Hayashi, T., Kunita, I., Nakamasu, A., Torisawa, Y.s., Nakayama, M.,
Magen, I., Chesselet, M.F., 2010. Genetic mouse models of Parkinson’s disease: the state Takigawa-Imamura, H., Kotera, H., Nishiyama, K., Miura, T., 2017. Integrating
of the art, Progress in brain research. Prog. Brain Res. 184, 53–87. https://doi.org/ perfusable vascular networks with a three-dimensional tissue in a microfluidic
10.1016/s0079-6123(10)84004-x, 2010. device. Integr. Biol. 9 (6), 506–518. https://doi.org/10.1039/c7ib00024c.
Maj, J., Rogóż, Z., Skuza, G., Kołodziejczyk, K., 1997. The behavioural effects of Neumann, J., Bras, J., Deas, E., O’Sullivan, S.S., Parkkinen, L., Lachmann, R.H., Li, A.,
pramipexole, a novel dopamine receptor agonist. Eur. J. Pharmacol. 324 (1), 31–37. Holton, J., Guerreiro, R., Paudel, R., 2009. Glucocerebrosidase mutations in clinical
https://doi.org/10.1016/s0014-2999(97)00066-6. and pathologically proven Parkinson’s disease. Brain 132 (Pt 7), 1783–1794.
Marotta, N., Kim, S., Krainc, D., 2020. Organoid and pluripotent stem cells in Parkinson’s https://doi.org/10.1093/brain/awp044.
disease modeling: an expert view on their value to drug discovery. Expet Opin. Drug Neustadt, B.R., Liu, H., Hao, J., Greenlee, W.J., Stamford, A.W., Foster, C., Arik, L.,
Discov. 15 (4), 427–441. https://doi.org/10.1080/17460441.2020.1703671. Lachowicz, J., Zhang, H., Bertorelli, R., 2009. Potent and selective adenosine A2A
Marton, R.M., Pasca, S.P., 2020. Organoid and assembloid technologies for investigating receptor antagonists: 1, 2, 4-Triazolo [1, 5-c] pyrimidines. Bioorganic & medicinal
cellular crosstalk in human brain development and disease. Trends Cell Biol. 30 (2), chemistry letters. Bioorg. Med. Chem. Lett. 19 (3), 967–971. https://doi.org/
133–143. https://doi.org/10.1016/j.tcb.2019.11.004. 10.1016/j.bmcl.2008.11.075.
Marxreiter, F., Nuber, S., Kandasamy, M., Klucken, J., Aigner, R., Burgmayer, R., Nguyen, H.N., Byers, B., Cord, B., Shcheglovitov, A., Byrne, J., Gujar, P., Kee, K.,
Couillard-Despres, S., Riess, O., Winkler, J., Winner, B., 2009. Changes in adult Schüle, B., Dolmetsch, R.E., Langston, W., 2011. LRRK2 mutant iPSC-derived DA
olfactory bulb neurogenesis in mice expressing the A30P mutant form of alpha- neurons demonstrate increased susceptibility to oxidative stress. Cell Stem Cell 8 (3),
synuclein. Eur. J. Neurosci. 29 (5), 879–890. 267–280. https://doi.org/10.1016/j.stem.2011.01.013.
Masliah, E., Rockenstein, E., Veinbergs, I., Mallory, M., Hashimoto, M., Takeda, A., Nisar, R., Hanson, P.S., He, L., Taylor, R.W., Blain, P.G., Morris, C.M., 2015. Diquat
Sagara, Y., Sisk, A., Mucke, L., 2000. Dopaminergic loss and inclusion body causes caspase-independent cell death in SH-SY5Y cells by production of ROS
formation in α-synuclein mice: implications for neurodegenerative disorders. Science independently of mitochondria. Arch. Toxicol. 89, 1811–1825. https://doi.org/
287, 1265–1269. https://doi.org/10.1111/j.1460-9568.2009.06641.x. 10.1007/s00204-015-1453-5.
Mata, I.F., Wedemeyer, W.J., Farrer, M.J., Taylor, J.P., Gallo, K.A., 2006. LRRK2 in Niso-Santano, M., González-Polo, R.A., Bravo-San Pedro, J.M., Gómez-Sánchez, R.,
Parkinson’s disease: protein domains and functional insights. Trends Neurosci. 29 Lastres-Becker, I., Ortiz-Ortiz, M.A., Soler, G., Morán, J.M., Cuadrado, A., Fuentes, J.
(5), 286–293. https://doi.org/10.1016/j.tins.2006.03.006. M., 2010. Activation of apoptosis signal-regulating kinase 1 is a key factor in
Mazzulli, J.R., Zunke, F., Tsunemi, T., Toker, N.J., Jeon, S., Burbulla, L.F., Patnaik, S., paraquat-induced cell death: modulation by the Nrf2/Trx axis. Free Radic. Biol. Med.
Sidransky, E., Marugan, J.J., Sue, C.M., 2016. Activation of β-glucocerebrosidase 48 (10), 1370–1381. https://doi.org/10.1016/j.freeradbiomed.2010.02.024.
19
Niswender, C.M., Johnson, K.A., Weaver, C.D., Jones, C.K., Xiang, Z., Luo, Q., increases risk of Parkinson’s disease via a dominant-negative mechanism. Brain 140
Rodriguez, A.L., Marlo, J.E., de Paulis, T., Thompson, A.D., 2008. Discovery, (1), 98–117. https://doi.org/10.1093/brain/aww261.
characterization, and antiparkinsonian effect of novel positive allosteric modulators Rahman, M.M., Chakraborti, R.R., Potol, M.A., Abir, A.H., Sharmin, O., Alam, M.,
of metabotropic glutamate receptor 4. Mol. Pharmacol. 74 (5), 1345–1358. https:// Khan, M.F.R., Afrin, R., Jannat, H., Wadud, R., 2020. Epalrestat improves motor
doi.org/10.1124/mol.108.049551. symptoms by reducing oxidative stress and inflammation in the reserpine induced
Ohta, E., Kawakami, F., Kubo, M., Obata, F., 2013. Dominant-negative effects of LRRK2 mouse model of Parkinson’s disease. Animal Model Exp. Méd. 3 (1), 9–21. https://
heterodimers: a possible mechanism of neurodegeneration in Parkinson’s disease doi.org/10.1002/ame2.12097.
caused by LRRK2 I2020T mutation. Biochem. Biophys. Res. Commun. 430 (2), 560. Rai, S.N., Singh, P., 2020. Advancement in the modelling and therapeutics of Parkinson’s
https://doi.org/10.1016/j.bbrc.2012.11.113, 560. disease. J. Chem. Neuroanat. 104, 101752 https://doi.org/10.1016/j.
Oliveira, L., Falomir-Lockhart, L.J., Botelho, M., Lin, K., Wales, P., Koch, J., Gerhardt, E., jchemneu.2020.101752.
Taschenberger, H., Outeiro, T., Lingor, P., 2015. Elevated α-synuclein caused by Raimondi, M.T., Albani, D., Giordano, C., 2019. An organ-on-a-chip engineered platform
SNCA gene triplication impairs neuronal differentiation and maturation in to study the microbiota–gut–brain axis in neurodegeneration. Trends Mol. Med. 25
Parkinson’s patient-derived induced pluripotent stem cells. Cell Death Dis. 6 (11), (9), 737–740. https://doi.org/10.1016/j.molmed.2019.07.006.
e1994 https://doi.org/10.1038/cddis.2015.318. Recasens, A., Dehay, B., 2014. Alpha-synuclein spreading in Parkinson’s disease. Front.
Oliveras-Salvá, M., Macchi, F., Coessens, V., Deleersnijder, A., Gérard, M., Van der Neuroanat. 8, 159. https://doi.org/10.3389/fnana.2014.00159.
Perren, A., Van den Haute, C., Baekelandt, V., 2014. Alpha-synuclein-induced Reiner, O., Sapir, T., Parichha, A., 2021. Using multi-organ culture systems to study
neurodegeneration is exacerbated in PINK1 knockout mice. Neurobiol. Aging 35 Parkinson’s disease. Mol. Psychiatr. 26 (3), 725–735. https://doi.org/10.1038/
(11), 2625–2636. https://doi.org/10.1016/j.neurobiolaging.2014.04.032. s41380-020-00936-8.
Oliveras-Salvá, M., Van der Perren, A., Casadei, N., Stroobants, S., Nuber, S., Ren, Y., Jiang, H., Ma, D., Nakaso, K., Feng, J., 2011. Parkin degrades estrogen-related
D’Hooge, R., Van den Haute, C., Baekelandt, V., 2013. rAAV2/7 vector-mediated receptors to limit the expression of monoamine oxidases. Hum. Mol. Genet. 20 (6),
overexpression of alpha-synuclein in mouse substantia nigra induces protein 1074–1083. https://doi.org/10.1093/hmg/ddq550.
aggregation and progressive dose-dependent neurodegeneration. Mol. Renner, H., Schöler, H.R., Bruder, J., 2021. Combining automated organoid workflows
Neurodegener. 8, 44–57. https://doi.org/10.1186/1750-1326-8-44. with artificial intelligence-based analyses: opportunities to build a new generation of
Ordonez-Librado, J.L., Anaya-Martinez, V., Gutierrez-Valdez, A.L., Colín-Barenque, L., interdisciplinary high-throughput screens for Parkinson’s disease and beyond. Mov.
Montiel-Flores, E., Avila-Costa, M.R., 2011. Manganese inhalation as a Parkinson Disord. 36 (12), 2745–2762. https://doi.org/10.1002/mds.28775.
disease model. Parkinsons Dis., 612989 https://doi.org/10.4061/2011/612989, Ricke, K.M., Paß, T., Kimoloi, S., Fährmann, K., Jüngst, C., Schauss, A., Baris, O.R.,
2011. Aradjanski, M., Trifunovic, A., Faelker, T.M., 2020. Mitochondrial dysfunction
Pagano, G., Niccolini, F., Politis, M., 2016. Imaging in Parkinson’s disease. Clin. Med. 16 combined with high calcium load leads to impaired antioxidant defense underlying
(4), 371–375. https://doi.org/10.7861/clinmedicine.16-4-371. the selective loss of nigral dopaminergic neurons. J. Neurosci. 40 (9), 1975–1986.
Palacino, J.J., Sagi, D., Goldberg, M.S., Krauss, S., Motz, C., Wacker, M., Klose, J., https://doi.org/10.1523/jneurosci.1345-19.2019.
Shen, J., 2004. Mitochondrial dysfunction and oxidative damage in parkin-deficient Rijntjes, M., Meyer, P.T., 2019. No free lunch with herbal preparations: lessons from a
mice. J. Biol. Chem. 279 (18), 18614–18622. https://doi.org/10.1074/jbc. case of parkinsonism and depression due to herbal medicine containing reserpine.
m401135200. Front. Neurol. 10, 634. https://doi.org/10.3389/fneur.2019.00634.
Paris, I., Lozano, J., Cardenas, S., Perez-Pastene, C., Saud, K., Fuentes, P., Caviedes, P., Rizek, P., Kumar, N., Jog, M.S., 2016. An update on the diagnosis and treatment of
Dagnino-Subiabre, A., Raisman-Vozari, R., Shimahara, T., Kostrzewa, J.P., Chi, D., Parkinson disease. CMAJ (Can. Med. Assoc. J.) 188 (16), 1157–1165. https://doi.
Kostrzewa, R.M., Caviedes, R., Segura-Aguilar, J., 2008. The catecholaminergic org/10.1503/cmaj.151179.
RCSN-3 cell line: a model to study dopamine metabolism. Neurotox. Res. 13 (3–4), Robledo, P., Feger, J., 1991. Acute monoaminergic depletion in the rat potentiates the
221–230. https://doi.org/10.1007/bf03033505. excitatory effect of the subthalamic nucleus in the substantia nigra pars reticulata
Parrella, E., Bellucci, A., Porrini, V., Benarese, M., Lanzillotta, A., Faustini, G., but not in the pallidal complex. J. Neural Transm. Gen. Sect. 86 (2), 115–126.
Longhena, F., Abate, G., Uberti, D., Pizzi, M., 2019. NF-κB/c-Rel deficiency causes https://doi.org/10.1007/bf01250572.
Parkinson’s disease-like prodromal symptoms and progressive pathology in mice. Rockenstein, E., Mallory, M., Hashimoto, M., Song, D., Shults, C.W., Lang, I., Masliah, E.,
Transl. Neurodegener. 8, 16. https://doi.org/10.1186/s40035-019-0154-z. 2002. Differential neuropathological alterations in transgenic mice expressing
Parrella, E., Del Gallo, F., Porrini, V., Gussago, C., Benarese, M., Fabene, P.F., Pizzi, M., α-synuclein from the platelet-derived growth factor and Thy-1 promoters.
2022. Age-dependent neuropsychiatric symptoms in the NF-κB/c-Rel knockout J. Neurosci. Res. 68 (5), 568–578. https://doi.org/10.1002/jnr.10231.
mouse model of Parkinson’s disease. Front. Behav. Neurosci. 16, 831664 https://doi. Rossi, A., Berger, K., Chen, H., Leslie, D., Mailman, R.B., Huang, X., 2018. Projection of
org/10.3389/fnbeh.2022.831664. the prevalence of Parkinson’s disease in the coming decades: revisited. Mov. Disord.
Paterna, J.C., Leng, A., Weber, E., Feldon, J., Büeler, H., 2007. DJ-1 and Parkin modulate 33 (1), 156–159. https://doi.org/10.1002/mds.27063.
dopamine-dependent behavior and inhibit MPTP-induced nigral dopamine neuron Rousseaux, M.W., Marcogliese, P.C., Qu, D., Hewitt, S.J., Seang, S., Kim, R.H., Slack, R.
loss in mice. Mol. Ther. 15 (4), 698–704. https://doi.org/10.1038/sj.mt.6300067. S., Schlossmacher, M.G., Lagace, D.C., Mak, T.W., 2012. Progressive dopaminergic
Paul, S., Maindarkar, M., Saxena, S., Saba, L., Turk, M., Kalra, M., Krishnan, P.R., Suri, J. cell loss with unilateral-to-bilateral progression in a genetic model of Parkinson
S., 2022. Bias investigation in artificial intelligence systems for early detection of disease. Proc. Natl. Acad. Sci. U. S. A 109 (39), 15918–15923. https://doi.org/
Parkinson’s disease: a narrative review. Diagnostics 12 (1), 166. https://doi.org/ 10.1073/pnas.1205102109.
10.3390/diagnostics12010166. Rovini, E., Maremmani, C., Cavallo, F., 2017. How wearable sensors can support
Perez, F.A., Palmiter, R.D., 2005. Parkin-deficient mice are not a robust model of Parkinson’s disease diagnosis and treatment: a systematic review. Front. Neurosci.
parkinsonism. Proc. Natl. Acad. Sci. U. S. A 102 (6), 2174–2179. https://doi.org/ 11, 555. https://doi.org/10.3389/fnins.2017.00555.
10.1073/pnas.0409598102. Rudenko, I.N., Cookson, M.R., 2014. Heterogeneity of leucine-rich repeat kinase 2
Periquet, M., Corti, O., Jacquier, S., Brice, A., 2005. Proteomic analysis of parkin mutations: genetics, mechanisms and therapeutic implications. Neurotherapeutics
knockout mice: alterations in energy metabolism, protein handling and synaptic 11 (4), 738–750. https://doi.org/10.1007/s13311-014-0284-z.
function. J. Neurochem. 95 (5), 1259–1276. https://doi.org/10.1111/j.1471- Rui, Q., Ni, H., Li, D., Gao, R., Chen, G., 2018. The role of LRRK2 in neurodegeneration of
4159.2005.03442.x. Parkinson disease. Curr. Neuropharmacol. 16 (9), 1348–1357. https://doi.org/
Picollet-D’hahan, N., Zuchowska, A., Lemeunier, I., Le Gac, S., 2021. Multiorgan-on-a- 10.2174/1570159x16666180222165418.
Chip: a systemic approach to model and decipher inter-organ communication. Rutherford, N.J., Moore, B.D., Golde, T.E., Giasson, B.I., 2014. Divergent effects of the
Trends Biotechnol. 39 (8), 788–810. https://doi.org/10.1016/j.tibtech.2020.11.014. H50Q and G51D SNCA mutations on the aggregation of α-synuclein. J. Neurochem.
Pizzi, M., Spano, P., 2006. Distinct roles of diverse nuclear factor-κB complexes in 131 (6), 859–867. https://doi.org/10.1111/jnc.12806.
neuropathological mechanisms. Eur. J. Pharmacol. 545 (1), 22–28. https://doi.org/ Ryan, S.D., Dolatabadi, N., Chan, S.F., Zhang, X., Akhtar, M.W., Parker, J., Soldner, F.,
10.1016/j.ejphar.2006.06.027. Sunico, C.R., Nagar, S., Talantova, M., 2013. Isogenic human iPSC Parkinson’s model
Porrini, V., Mota, M., Parrella, E., Bellucci, A., Benarese, M., Faggi, L., Tonin, P., shows nitrosative stress-induced dysfunction in MEF2-PGC1α transcription. Cell 155
Spano, P.F., Pizzi, M., 2017. Mild inflammatory profile without gliosis in the c-Rel (6), 1351–1364. https://doi.org/10.1016/j.cell.2013.11.009.
deficient mouse modeling a late-onset Parkinsonism. Front. Aging Neurosci. 9, 229. Sabate-Soler, S., Nickels, S.L., Saraiva, C., Berger, E., Dubonyte, U., Barmpa, K., Lan, Y.J.,
https://doi.org/10.3389/fnagi.2017.00229. Kouno, T., Jarazo, J., Robertson, G., 2022. Microglia integration into human
Potashkin, J., Blume, S., Runkle, N., 2011. Limitations of animal models of Parkinson’s midbrain organoids leads to increased neuronal maturation and functionality. Glia
disease. Parkinsons Dis. 2011, 658083 https://doi.org/10.4061/2011/658083. 70 (7), 1267–1288. https://doi.org/10.1002/glia.24167.
Paul, K.C., Ritz, B., 2022. Epidemiology meets toxicogenomics: mining toxicologic Saleem, S., Kannan, R.R., 2018. Zebrafish: an emerging real-time model system to study
evidence in support of an untargeted analysis of pesticides exposure and Parkinson’s Alzheimer’s disease and neurospecific drug discovery. Cell Death Dis. 4, 45. https://
disease. Environ. Int. 170, 107613 https://doi.org/10.1016/j.envint.2022.107613. doi.org/10.1038/s41420-018-0109-7.
Prajapati, S.K., Garabadu, D., Krishnamurthy, S., 2017. Coenzyme Q10 prevents Sanberg, P.R., Bunsey, M.D., Giordano, M., Norman, A.B., 1988. The catalepsy test: its
mitochondrial dysfunction and facilitates pharmacological activity of atorvastatin in ups and downs. Behav. Neurosci. 102 (5), 748–759. https://doi.org/10.1037//0735-
6-OHDA induced dopaminergic toxicity in rats. Neurotox. Res. 31 (4), 478–492. 7044.102.5.748.
https://doi.org/10.1007/s12640-016-9693-6. Sanders, L.H., Laganière, J., Cooper, O., Mak, S.K., Vu, B.J., Huang, Y.A., Paschon, D.E.,
Prots, I., Grosch, J., Brazdis, R.-M., Simmnacher, K., Veber, V., Havlicek, S., Vangipuram, M., Sundararajan, R., Urnov, F.D., 2014. LRRK2 mutations cause
Hannappel, C., Krach, F., Krumbiegel, M., Schütz, O., 2018. α-Synuclein oligomers mitochondrial DNA damage in iPSC-derived neural cells from Parkinson’s disease
induce early axonal dysfunction in human iPSC-based models of synucleinopathies. patients: reversal by gene correction. Neurobiol. Dis. 62, 381–386. https://doi.org/
Proc. Natl. Acad. Sci. U. S. A 115 (30), 7813–7818. https://doi.org/10.1073/ 10.1016/j.nbd.2013.10.013.
pnas.1713129115. Sang, T.-K., Chang, H.-Y., Lawless, G.M., Ratnaparkhi, A., Mee, L., Ackerson, L.C.,
Puschmann, A., Fiesel, F.C., Caulfield, T.R., Hudec, R., Ando, M., Truban, D., Hou, X., Maidment, N.T., Krantz, D.E., Jackson, G.R., 2007. A Drosophila model of mutant
Ogaki, K., Heckman, M.G., James, E.D., 2017. Heterozygous PINK1 p. G411S human parkin-induced toxicity demonstrates selective loss of dopaminergic neurons
20
and dependence on cellular dopamine. J. Neurosci. 27 (5), 981–992. https://doi. Spitz, S., Bolognin, S., Brandauer, K., Fuessl, J., Schuller, P., Schobesberger, S.,
org/10.1523/jneurosci.4810-06.2007. Jordan, C., Schaedl, B., Grillari, J., Wanzenboeck, H.D., 2022. Development of a
Santos, J.R., Cunha, J.A., Dierschnabel, A.L., Campêlo, C.L., Leão, A.H., Silva, A.F., multi-sensor integrated midbrain organoid-on-a-chip platform for studying
Engelberth, R.C., Izídio, G.S., Cavalcante, J.S., Abílio, V.C., 2013. Cognitive, motor Parkinson’s disease. 2022.2008.2019.504522. https://doi.org/10.1101/2022.08.19.
and tyrosine hydroxylase temporal impairment in a model of parkinsonism induced 504522.
by reserpine. Behav. Brain Res. 253, 68–77. https://doi.org/10.1016/j. Springer, W., Hoppe, T., Schmidt, E., Baumeister, R., 2005. A Caenorhabditis elegans
bbr.2013.06.031. Parkin mutant with altered solubility couples α-synuclein aggregation to proteotoxic
Schapira, A.H., 2015. Glucocerebrosidase and Parkinson disease: recent advances. Mol. stress. Hum. Mol. Genet. 14 (22), 3407–3423. https://doi.org/10.1093/hmg/
Cell. Neurosci. 66 (Pt A), 37–42. https://doi.org/10.1016/j.mcn.2015.03.013. ddi371.
Schmidt, N., Ferger, B., 2001. Neurochemical findings in the MPTP model of Parkinson’s Stayte, S., Vissel, B., 2014. Advances in non-dopaminergic treatments for Parkinson’s
disease. J. Neural. Transm. 108 (11), 1263–1282. https://doi.org/10.1007/ disease. Front. Neurosci. 8, 113. https://doi.org/10.3389/fnins.2014.00113.
s007020100004. Su, X., Maguire-Zeiss, K.A., Giuliano, R., Prifti, L., Venkatesh, K., Federoff, H.J., 2008.
Schober, A., 2004. Classic toxin-induced animal models of Parkinson’s disease: 6-OHDA Synuclein activates microglia in a model of Parkinson’s disease. Neurobiol. Aging 29
and MPTP. Cell Tissue Res. 318 (1), 215–224. https://doi.org/10.1007/s00441-004- (11), 1690–1701. https://doi.org/10.1016/j.neurobiolaging.2007.04.006.
0938-y. Suwijn, S.R., van Boheemen, C.J., de Haan, R.J., Tissingh, G., Booij, J., de Bie, R.M.,
Schöndorf, D.C., Aureli, M., McAllister, F.E., Hindley, C.J., Mayer, F., Schmid, B., 2015. The diagnostic accuracy of dopamine transporter SPECT imaging to detect
Sardi, S.P., Valsecchi, M., Hoffmann, S., Schwarz, L.K., 2014. iPSC-derived neurons nigrostriatal cell loss in patients with Parkinson’s disease or clinically uncertain
from GBA1-associated Parkinson’s disease patients show autophagic defects and parkinsonism: a systematic review. EJNMMI Res. 5, 12. https://doi.org/10.1186/
impaired calcium homeostasis. Nat. Commun. 5, 4028. https://doi.org/10.1038/ s13550-015-0087-1.
ncomms5028. Tain, L.S., Chowdhury, R.B., Tao, R.N., Plun-Favreau, H., Moisoi, N., Martins, L.M.,
Schwarting, R., Huston, J., 1996. Unilateral 6-hydroxydopamine lesions of meso-striatal Downward, J., Whitworth, A.J., Tapon, N.J.C.D., Differentiation, 2009. Drosophila
dopamine neurons and their physiological sequelae. Prog. Neurobiol. 49 (3), HtrA2 is dispensable for apoptosis but acts downstream of PINK1 independently
215–266. https://doi.org/10.1016/s0301-0082(96)00015-9. from Parkin. Cell Death Differ. 16 (8), 1118–1125. https://doi.org/10.1038/
Sebastianutto, I., Cenci, M.A., 2018. mGlu receptors in the treatment of Parkinson’s cdd.2009.23.
disease and L-DOPA-induced dyskinesia. Curr. Opin. Pharmacol. 38, 81–89. https:// Takahashi, N., Miner, L.L., Sora, I., Ujike, H., Revay, R.S., Kostic, V., Jackson-Lewis, V.,
doi.org/10.1016/j.coph.2018.03.003. Przedborski, S., Uhl, G.R., 1997. VMAT2 knockout mice: heterozygotes display
Sebel, L.E., Graves, S.M., Chan, C.S., Surmeier, D.J., 2017. Haloperidol selectively reduced amphetamine-conditioned reward, enhanced amphetamine locomotion, and
remodels striatal indirect pathway circuits. Neuropsychopharmacology 42 (4), enhanced MPTP toxicity. Proc. Natl. Acad. Sci. U. S. A 94 (18), 9938–9943. https://
963–973. https://doi.org/10.1038/npp.2016.173. doi.org/10.1073/pnas.94.18.9938.
See, W.Z.C., Naidu, R., Tang, K.S., 2022. Cellular and molecular events leading to Takahashi, R., Rogerio, R., Zanin, M., 1989. Maneb enhances MPTP neurotoxicity in
paraquat-induced apoptosis: mechanistic insights into Parkinson’s disease mice. Research communications in chemical pathology and pharmacology. Res.
pathophysiology. Mol. Neurobiol. 59 (6), 3353–3369. https://doi.org/10.1007/ Commun. Chem. Pathol . Pharmacol. 66 (1), 167–170. PMID:2616897.
s12035-022-02799-2. Tanaka, A., 2010. Parkin-mediated selective mitochondrial autophagy, mitophagy:
Seibler, P., Graziotto, J., Jeong, H., Simunovic, F., Klein, C., Krainc, D.J., 2011. parkin purges damaged organelles from the vital mitochondrial network. FEBS Lett.
Mitochondrial Parkin recruitment is impaired in neurons derived from mutant 584 (7), 1386–1392. https://doi.org/10.1016/j.febslet.2010.02.060.
PINK1 induced pluripotent stem cells. J. Neurosci. 31 (16), 5970–5976. https://doi. Tarrants, M.L., Denarié, M.F., Castelli-Haley, J., Millard, J., Zhang, D., 2010. Drug
org/10.1523/jneurosci.4441-10.2011. therapies for Parkinson’s disease: a database analysis of patient compliance and
Segura-Aguilar, J., 2011. Catecholaminergic cell lines for the study of dopamine persistence. Am. J. Geriatr. Pharmacother. 8 (4), 374–383. https://doi.org/10.1016/
metabolism and neurotoxicity. In: Aschner, M., Suñol, C., Bal-Price, A. (Eds.), Cell j.amjopharm.2010.08.001.
Culture Techniques. Neuromethods, 56, pp. 383–402. https://doi.org/10.1007/978- Taylor, T.N., Caudle, W.M., Miller, G.W., 2011. VMAT2-deficient mice display nigral and
1-61779-077-5-19. extranigral pathology and motor and nonmotor symptoms of Parkinson’s disease.
Senoh, S., Creveling, C.R., Udenfriend, S., Witkop, B., 1959. Chemical, Enzymatic and Parkinsons Dis. 2011, 124165 https://doi.org/10.4061/2011/124165.
Metabolic Studies on the Mechanism of Oxidation of Dopamine1. J. Am. Chem. Soc. Taylor, T.N., Caudle, W.M., Shepherd, K.R., Noorian, A., Jackson, C.R., Iuvone, P.M.,
81 (23), 6236–6240. https://doi.org/10.1007/s00018-015-2101-1. Weinshenker, D., Greene, J.G., Miller, G.W., 2009. Nonmotor symptoms of
Sharon, R., Bar-Joseph, I., Mirick, G.E., Serhan, C.N., Selkoe, D.J., 2003. Altered fatty Parkinson’s disease revealed in an animal model with reduced monoamine storage
acid composition of dopaminergic neurons expressing α-synuclein and human brains capacity. J. Neurosci. 29 (25), 8103–8113. https://doi.org/10.1523/jneurosci.1495-
with α-synucleinopathies. J. Biol. Chem. 278 (50), 49874–49881. https://doi.org/ 09.2009.
10.1074/jbc.m309127200. Tejchman, A., Znój, A., Chlebanowska, P., Frączek-Szczypta, A., Majka, M., 2020. Carbon
Shendelman, S., Jonason, A., Martinat, C., Leete, T., Abeliovich, A., 2004. DJ-1 is a fibers as a new type of scaffold for midbrain organoid development. Int. J. Mol. Sci.
redox-dependent molecular chaperone that inhibits α-synuclein aggregate 21 (17), 5959. https://doi.org/10.3390/ijms21175959.
formation. PLoS Biol. 2 (11), e362. https://doi.org/10.1371/journal.pbio.0020362. Terron, A., Bal-Price, A., Paini, A., Monnet-Tschudi, F., Bennekou, S.H., Viviani, E.W.E.
Sheng, D., Qu, D., Kwok, K.H.H., Ng, S.S., Lim, A.Y.M., Aw, S.S., Lee, C.W.H., Sung, W.K., M., Leist, M., Schildknecht, S., 2018. An adverse outcome pathway for parkinsonian
Tan, E.K., Lufkin, T., 2010. Deletion of the WD40 domain of LRRK2 in Zebrafish motor deficits associated with mitochondrial complex I inhibition. Arch. Toxicol. 92
causes Parkinsonism-like loss of neurons and locomotive defect. PLoS Genet. 6 (4), (1), 41–82. https://doi.org/10.1007/s00204-017-2133-4.
e1000914 https://doi.org/10.1371/journal.pgen.1000914. Terzioglu, M., Galter, D., 2008. Parkinson’s disease: genetic versus toxin-induced rodent
Shook, B.C., Rassnick, S., Osborne, M.C., Davis, S., Westover, L., Boulet, J., Hall, D., models. FEBS J. 275 (7), 1384–1391. https://doi.org/10.1111/j.1742-
Rupert, K.C., Heintzelman, G.R., Hansen, K., 2010. In vivo characterization of a dual 4658.2008.06302.x.
adenosine A2A/A1 receptor antagonist in animal models of Parkinson’s disease. Thiruchelvam, M., Powers, J., Cory-Slechta, D., Richfield, E., 2004. Risk factors for
J. Med. Chem. 53 (22), 8104–8115. https://doi.org/10.1021/jm100971t. dopaminergic neuron loss in human α-synuclein transgenic mice. Eur. J. Neurosci.
Shrestha, S., Parks, C.G., Umbach, D.M., Richards-Barber, M., Hofmann, J.N., Chen, H., 19 (4), 845–854. https://doi.org/10.1111/j.0953-816x.2004.03139.x.
Blair, A., Freeman, L.E.B., Sandler, D.P., 2020. Pesticide use and incident Parkinson’s Tolosa, E., Botta-Orfila, T., Morató, X., Calatayud, C., Ferrer-Lorente, R., Martí, M.-J.,
disease in a cohort of farmers and their spouses. Environ. Res. 191, 110186 https:// Fernández, M., Gaig, C., Raya, Á., Consiglio, A., 2018. MicroRNA alterations in iPSC-
doi.org/10.1016/j.envres.2020.110186. derived dopaminergic neurons from Parkinson disease patients. Neurobiol. Aging 69,
Simons, E., Fleming, S.M., 2023. Role of rodent models in advancing precision medicine 283–291. https://doi.org/10.1016/j.neurobiolaging.2018.05.032.
for Parkinson’s disease. Handb. Clin. Neurol. 193, 3–16. https://doi.org/10.10 Trapecar, M., Wogram, E., Svoboda, D., Communal, C., Omer, A., Lungjangwa, T.,
16/B978-0-323-85555-6.00002-3. Sphabmixay, P., Velazquez, J., Schneider, K., Wright, C.W.J.S.A., 2021. Human
Smeyne, R.J., Jackson-Lewis, V., 2005. The MPTP model of Parkinson’s disease. Brain physiomimetic model integrating microphysiological systems of the gut, liver, and
Res. Mol. Brain Res. 134 (1), 57–66. https://doi.org/10.1016/j. brain for studies of neurodegenerative diseases. Sci. Adv. 7 (5), eabd1707 https://
molbrainres.2004.09.017. doi.org/10.1126/sciadv.abd1707.
Smirnova, L., Harris, G., Delp, J., Valadares, M., Pamies, D., Hogberg, H.T., Tsika, E., Moore, D.J., 2013. Contribution of GTPase activity to LRRK2-associated
Waldmann, T., Leist, M., Hartung, T.J.A.o.t., 2016. A LUHMES 3D dopaminergic Parkinson disease. Small GTPases 4 (3), 164–170. https://doi.org/10.4161/
neuronal model for neurotoxicity testing allowing long-term exposure and cellular sgtp.25130.
resilience analysis. Arch. Toxicol. 90 (11), 2725–2743. https://doi.org/10.1007/ Uçar, B., Stefanova, N., Humpel, C., 2022. Spreading of aggregated α-synuclein in sagittal
s00204-015-1637-z. organotypic mouse brain slices. Biomolecules 12 (2), 163. https://doi.org/10.3390/
Smith, W.W., Pei, Z., Jiang, H., Dawson, V.L., Dawson, T.M., Ross, C.A., 2006. Kinase biom12020163.
activity of mutant LRRK2 mediates neuronal toxicity. Nat. Neurosci. 9 (10), Uversky, V.N., 2004. Neurotoxicant-induced animal models of Parkinson’s disease:
1231–1233. https://doi.org/10.1038/nn1776. understanding the role of rotenone, maneb and paraquat in neurodegeneration. Cell
Smits, L.M., Reinhardt, L., Reinhardt, P., Glatza, M., Monzel, A.S., Stanslowsky, N., Tissue 318 (1), 225–241. https://doi.org/10.1007/s00441-004-0937-z.
Rosato-Siri, M.D., Zanon, A., Antony, P.M., Bellmann, J., 2019. Modeling Uzquiano, A., Kedaigle, A.J., Pigoni, M., Paulsen, B., Adiconis, X., Kim, K., Faits, T.,
Parkinson’s disease in midbrain-like organoids. NPJ Parkinsons Dis 5, 5. https://doi. Nagaraja, S., Antón-Bolaños, N., Gerhardinger, C.J.C., 2022. Proper acquisition of
org/10.1038/s41531-019-0078-4. cell class identity in organoids allows definitionof fate specification programs of the
Sozzi, E., Kajtez, J., Bruzelius, A., Wesseler, M.F., Nilsson, F., Birtele, M., Larsen, N.B., human cerebral cortex. Cell 185 (20), 3770–3788.e27. https://doi.org/10.1016/j.
Ottosson, D.R., Storm, P., Parmar, M., 2022. Silk scaffolding drives self-assembly of cell.2022.09.010.
functional and mature human brain organoids. Front. Cell Dev. Biol. 10, 1023279 Ved, R., Saha, S., Westlund, B., Perier, C., Burnam, L., Sluder, A., Hoener, M.,
https://doi.org/10.3389/fcell.2022.1023279. Rodrigues, C.M., Alfonso, A., Steer, C., 2005. Similar patterns of mitochondrial
vulnerability and rescue induced by genetic modification of α-synuclein, parkin, and
21
DJ-1 in Caenorhabditis elegans. J. Biol. Chem. 280 (52), 42655–42668. https://doi. Yeap, Y.J., Teddy, T.J., Lee, M.J., Goh, M., Lim, K.L., 2023. From 2D to 3D: development
org/10.1074/jbc.m505910200. of monolayer dopaminergic neuronal and midbrain organoid cultures for
Vekrellis, K., Xilouri, M., Emmanouilidou, E., Rideout, H.J., Stefanis, L., 2011. Parkinson’s disease modeling and regenerative therapy. Int. J. Mol. Sci. 24 (3), 2523.
Pathological roles of α-synuclein in neurological disorders. Lancet Neurol. 10 (11), https://doi.org/10.3390/ijms24032523.
1015–1025. https://doi.org/10.1016/s1474-4422(11)70213-7. Yiğit, E.N., Sönmez, E., Söğüt, M.S., Çakır, T., Kurnaz, I.A., 2018. Validation of an in-
Volpicelli-Daley, L.A., Abdelmotilib, H., Liu, Z., Stoyka, L., Daher, J.P.L., Milnerwood, A. vitro Parkinson’s disease model for the study of neuroprotection. Proceedings 2 (25),
J., Unni, V.K., Hirst, W.D., Yue, Z., Zhao, H.T., 2016. G2019S-LRRK2 expression 1559. https://doi.org/10.3390/proceedings2251559, 2018.
augments α-synuclein sequestration into inclusions in neurons. J. Neurosci. 36 (28), Yokota, T., Sugawara, K., Ito, K., Takahashi, R., Ariga, H., Mizusawa, H., 2003. Down
7415–7427. https://doi.org/10.1523/jneurosci.3642-15.2016. regulation of DJ-1 enhances cell death by oxidative stress, ER stress, and proteasome
Von Coelln, R., Thomas, B., Savitt, J.M., Lim, K.L., Sasaki, M., Hess, E.J., Dawson, V.L., inhibition. Biochem. Biophys. Res. Commun. 312 (4), 1342–1348. https://doi.org/
Dawson, T.M., 2004. Loss of locus coeruleus neurons and reduced startle in parkin 10.1016/j.bbrc.2003.11.056.
null mice. Proc. Natl. Acad. Sci. U. S. A 101 (29), 10744–10749. https://doi.org/ Yu, W.H., Matsuoka, Y., Sziráki, I., Hashim, A., LaFrancois, J., Sershen, H., Duff, K.E.,
10.1073/pnas.0401297101. 2008. Increased dopaminergic neuron sensitivity to 1-methyl-4-phenyl-1, 2, 3, 6-
Wang, Y., Chen, X., Wang, Y., Li, S., Cai, H., Le, W., 2021. The essential role of tetrahydropyridine (MPTP) in transgenic mice expressing mutant A53T α-synuclein.
transcription factor Pitx3 in preventing mesodiencephalic dopaminergic Neurochem. Res. 33 (5), 902–911. https://doi.org/10.1007/s11064-007-9533-4.
neurodegeneration and maintaining neuronal subtype identities during aging. Cell Yuan, H., Sarre, S., Ebinger, G., Michotte, Y., 2005. Histological, behavioural and
Death Dis. 12 (11), 1008. https://doi.org/10.1038/s41419-021-04319-x. neurochemical evaluation of medial forebrain bundle and striatal 6-OHDA lesions as
Whitworth, A.J., Lee, J.R., Ho, V.M.-W., Flick, R., Chowdhury, R., McQuibban, G.A., rat models of Parkinson’s disease. J. Neurosci. Methods 144 (1), 35–45. https://doi.
2008. Rhomboid-7 and HtrA2/Omi act in a common pathway with the Parkinson’s org/10.1016/j.jneumeth.2004.10.004.
disease factors Pink1 and Parkin. Dis. Model Mech. 1 (2–3), 168–174. https://doi. Zagare, A., Barmpa, K., Smajic, S., Smits, L.M., Grzyb, K., Grünewald, A., Skupin, A.,
org/10.1242/dmm.000109. Nickels, S.L., Schwamborn, J.C., 2022. Midbrain organoids mimic early embryonic
Wilson, W.W., Shapiro, L.P., Bradner, J.M., Caudle, W.M., 2014. Developmental neurodevelopment and recapitulate LRRK2-p. Gly2019Ser-associated gene
exposure to the organochlorine insecticide endosulfan damages the nigrostriatal expression. Am. J. Hum. Genet. 109 (2), 311–327. https://doi.org/10.1016/j.
dopamine system in male offspring. Neurotoxicology 44, 279–287. https://doi.org/ ajhg.2021.12.009.
10.1016/j.neuro.2014.07.008. Zhang, L., Cen, L., Qu, S., Wei, L., Mo, M., Feng, J., Sun, C., Xiao, Y., Luo, Q., Li, S.J.,
Woodard, C.M., Campos, B.A., Kuo, S.-H., Nirenberg, M.J., Nestor, M.W., Zimmer, M., 2016. Enhancing beta-catenin activity via GSK3beta inhibition protects PC12 cells
Mosharov, E.V., Sulzer, D., Zhou, H., Paull, D., 2014. iPSC-derived dopamine against rotenone toxicity through Nurr1 induction. PLoS One 11 (4), e0152931.
neurons reveal differences between monozygotic twins discordant for Parkinson’s https://doi.org/10.1371/journal.pone.0152931.
disease. Cell Rep. 9 (4), 1173–1782. https://doi.org/10.1016/j.celrep.2014.10.023. Zhang, L., Shimoji, M., Thomas, B., Moore, D.J., Yu, S.W., Marupudi, N.I., Torp, R.,
Xi, Y., Noble, S., Ekker, M., 2011. Modeling neurodegeneration in zebrafish. Curr. Torgner, I.A., Ottersen, O.P., Dawson, T.M., Dawson, V.L., 2005. Mitochondrial
Neurol. Neurosci. Rep. 11 (3), 274–282. https://doi.org/10.1007/s11910-011-0182- localization of the Parkinson’s disease related protein DJ-1: implications for
2. pathogenesis. Hum. Mol. Genet. 14 (14), 2063–2073. https://doi.org/10.1093/hmg/
Xi, Y., Ryan, J., Noble, S., Yu, M., Yilbas, A.E., Ekker, M., 2010. Impaired dopaminergic ddi211.
neuron development and locomotor function in zebrafish with loss of pink1 function. Zhang, X.-m., Yin, M., Zhang, M.H., 2014. Cell-based assays for Parkinson’s disease using
Eur. J. Neurosci. 31 (4), 623–633. https://doi.org/10.1111/j.1460- differentiated human LUHMES cells. Acta Pharmacol. Sin. 35 (7), 945–956. https://
9568.2010.07091.x. doi.org/10.1038/aps.2014.36.
Xicoy, H., Wieringa, B., Martens, G.J., 2017. The SH-SY5Y cell line in Parkinson’s disease Zhang, Y., Gao, J., Chung, K.K., Huang, H., Dawson, V.L., Dawson, T.M., 2000. Parkin
research: a systematic review. Mol. Neurodegener. 12 (1), 10–21. https://doi.org/ functions as an E2-dependent ubiquitin–protein ligase and promotes the degradation
10.1186/s13024-017-0149-0. of the synaptic vesicle-associated protein, CDCrel-1. Proc. Natl. Acad. Sci. U. S. A. 97
Xie, H.r., Hu, L.s., Li, G.y., 2010. SH-SY5Y human neuroblastoma cell line: in vitro cell (24), 13354–13359. https://doi.org/10.1073/pnas.240347797.
model of dopaminergic neurons in Parkinson’s disease. Chin Med J (Engl). 123 (8), Zhang, Z., Kang, S.S., Liu, X., Ahn, E.H., Zhang, Z., He, L., Iuvone, P.M., Duong, D.M.,
1086–1092. https://doi.org/10.1186/s13024-017-0149-0. Seyfried, N.T., Benskey, M.J., 2017. Asparagine endopeptidase cleaves α-synuclein
Xiong, Y., Dawson, T.M., Dawson, V.L., 2017. Models of LRRK2-associated Parkinson’s and mediates pathologic activities in Parkinson’s disease. Nat. Struct. Mol. Biol. 24
disease. Adv. Neurobiol. 14, 163–191. https://doi.org/10.1007/978-3-319-49969-7_ (8), 632–642. https://doi.org/10.1038/nsmb.3433.
9, 2017. Zheng, J., Zhang, X., Zhen, X., 2018. Development of adenosine A2A receptor antagonists
Yael, D., Zeef, D.H., Sand, D., Moran, A., Katz, D.B., Cohen, D., Temel, Y., Bar-Gad, I., for the treatment of Parkinson’s disease: a recent update and challenge. ACS Chem.
2013. Haloperidol-induced changes in neuronal activity in the striatum of the freely Neurosci. 10 (2), 783–791. https://doi.org/10.1021/acschemneuro.8b00313.
moving rat. Front. Syst. Neurosci. 7, 110. https://doi.org/10.3389/ Zhou, Q., Zhang, H., Wu, Q., Shi, J., Zhou, S., biology, m., 2017. Pharmacological
fnsys.2013.00110. manipulations of autophagy modulate paraquat-induced cytotoxicity in PC12 cells.
Yang, D., Thomas, J.M., Li, T., Lee, Y., Liu, Z., Smith, W.W., 2018. The Drosophila hep Int. J. Biochem. Mol. Biol. 8 (2), 13–22. http://www.ncbi.nlm.nih.gov/pmc/artic
pathway mediates Lrrk2-induced neurodegeneration. Biochem. Cell. Biol. 96 (4), les/pmc5498847/.
441–449. https://doi.org/10.1139/bcb-2017-0262. Zimprich, A., Biskup, S., Leitner, P., Lichtner, P., Farrer, M., Lincoln, S., Kachergus, J.,
Yang, Y., Ouyang, Y., Yang, L., Beal, M.F., McQuibban, A., Vogel, H., Lu, B., 2008. Pink1 Hulihan, M., Uitti, R.J., Calne, D.B., 2004a. Mutations in LRRK2 cause autosomal-
regulates mitochondrial dynamics through interaction with the fission/fusion dominant parkinsonism with pleomorphic pathology. Neuron 44 (4), 601–617.
machinery. Proc. Natl. Acad. Sci. U. S. A 105 (19), 7070–7075. https://doi.org/ https://doi.org/10.1016/j.neuron.2004.11.005.
10.1073/pnas.0711845105. Zimprich, A., Biskup, S., Leitner, P., Lichtner, P., Farrer, M., Lincoln, S., Kachergus, J.,
Yang, Y., Yuan, Y., Zhang, G., Wang, H., Chen, Y.C., Liu, Y., Tarolli, C.G., Crepeau, D., Hulihan, M., Uitti, R.J., Calne, D.B., 2004b. Mutations in LRRK2 cause autosomal-
Bukartyk, J., Junna, M.R., 2022. Artificial intelligence-enabled detection and dominant parkinsonism with pleomorphic pathology. Neuron 44 (4), 601–617.
assessment of Parkinson’s disease using nocturnal breathing signals. Nat. Med. 28 https://doi.org/10.1016/j.neuron.2004.11.005.
(10), 2207–2215. https://doi.org/10.1038/s41591-022-01932-x.
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European Journal of Pharmacology 980 (2024) 176819

Contents lists available at ScienceDirect

European Journal of Pharmacology

Experimental models of Parkinson’s disease: Challenges and Opportunities

activity observed in typical

3. Genetic models et al., 2003; Hinkle et al., 2012)

In recent years, genetic models have been developed by manipu-

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